ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1154G>A (p.Arg385His)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(13); Benign(1); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000249.4(MLH1):c.1154G>A (p.Arg385His)
Variation ID: 140759 Accession: VCV000140759.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37025752 (GRCh38) [ NCBI UCSC ] 3: 37067243 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 6, 2017 May 1, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.1154G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Arg385His missense NM_001167617.3:c.860G>A NP_001161089.1:p.Arg287His missense NM_001167618.3:c.431G>A NP_001161090.1:p.Arg144His missense NM_001167619.3:c.431G>A NP_001161091.1:p.Arg144His missense NM_001258271.2:c.1154G>A NP_001245200.1:p.Arg385His missense NM_001258273.2:c.431G>A NP_001245202.1:p.Arg144His missense NM_001258274.3:c.431G>A NP_001245203.1:p.Arg144His missense NM_001354615.2:c.431G>A NP_001341544.1:p.Arg144His missense NM_001354616.2:c.431G>A NP_001341545.1:p.Arg144His missense NM_001354617.2:c.431G>A NP_001341546.1:p.Arg144His missense NM_001354618.2:c.431G>A NP_001341547.1:p.Arg144His missense NM_001354619.2:c.431G>A NP_001341548.1:p.Arg144His missense NM_001354620.2:c.860G>A NP_001341549.1:p.Arg287His missense NM_001354621.2:c.131G>A NP_001341550.1:p.Arg44His missense NM_001354622.2:c.131G>A NP_001341551.1:p.Arg44His missense NM_001354623.2:c.131G>A NP_001341552.1:p.Arg44His missense NM_001354624.2:c.80G>A NP_001341553.1:p.Arg27His missense NM_001354625.2:c.80G>A NP_001341554.1:p.Arg27His missense NM_001354626.2:c.80G>A NP_001341555.1:p.Arg27His missense NM_001354627.2:c.80G>A NP_001341556.1:p.Arg27His missense NM_001354628.2:c.1154G>A NP_001341557.1:p.Arg385His missense NM_001354629.2:c.1055G>A NP_001341558.1:p.Arg352His missense NM_001354630.2:c.1154G>A NP_001341559.1:p.Arg385His missense NC_000003.12:g.37025752G>A NC_000003.11:g.37067243G>A NG_007109.2:g.37403G>A LRG_216:g.37403G>A LRG_216t1:c.1154G>A LRG_216p1:p.Arg385His - Protein change
- R385H, R144H, R27H, R287H, R352H, R44H
- Other names
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- Canonical SPDI
- NC_000003.12:37025751:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00005
Exome Aggregation Consortium (ExAC) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MLH1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5624 | 5679 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Feb 17, 2023 | RCV000128876.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 27, 2022 | RCV000232561.9 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Oct 16, 2023 | RCV000409286.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 14, 2022 | RCV000484459.5 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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May 10, 2023 | RCV000657135.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000764490.2 | |
Lynch-like syndrome
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Uncertain significance (1) |
no assertion criteria provided
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Jul 1, 2019 | RCV001249936.1 |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 11, 2024 | RCV003997466.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001136401.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001307794.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(May 10, 2016)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000488610.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Mar 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000570352.6
First in ClinVar: Apr 29, 2017 Last updated: Apr 09, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal, breast, or other cancer (Ballinger … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal, breast, or other cancer (Ballinger et al., 2016; Wang et al., 2019; Fanale et al., 2022; Guindalini et al., 2022; Zhang et al., 2023); This variant is associated with the following publications: (PMID: 31391288, 27149842, 33042626, 31248605, 36215471, 27498913, 35223509, 30982232, 35264596, 36627197) (less)
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Benign
(Mar 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004018138.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants … (more)
This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. (less)
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Uncertain significance
(Oct 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV004171468.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
Comment:
The MLH1 c.1154G>A (p.Arg385His) missense change has a maximum subpopulation frequency of 0.019% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious … (more)
The MLH1 c.1154G>A (p.Arg385His) missense change has a maximum subpopulation frequency of 0.019% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in one individual with Lynch syndrome-related colorectal cancer (PMID: 35223509), as well as in individuals with prostate cancer (PMID: 31248605), lung adenocarcinoma (PMID: 35280419), and familial breast/ovarian cancer (PMID: 30982232). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
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Uncertain significance
(Oct 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004195059.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely benign
(Sep 11, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000172733.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Muir-Torré syndrome
Mismatch repair cancer syndrome 1 Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000895561.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(Jan 14, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601346.2
First in ClinVar: Apr 29, 2017 Last updated: Jan 26, 2021 |
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Uncertain significance
(Nov 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919660.2
First in ClinVar: Jun 02, 2019 Last updated: Dec 24, 2022 |
Comment:
Variant summary: MLH1 c.1154G>A (p.Arg385His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: MLH1 c.1154G>A (p.Arg385His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251414 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (5.2e-05 vs 0.00071), allowing no conclusion about variant significance. c.1154G>A has been reported in the literature as a VUS in settings of multi-gene testing in at least one individual affected with Hereditary Nonpolyposis Colorectal Cancer (HNPCC)/Lynch Syndrome, and in individuals affected with prostate and other cancers (e.g. Wang_2019, Wei_2019, Li_2021, Fanale_2022). These reports do not provide unequivocal conclusions about association of the variant with HNPCC/Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as VUS (n=9) and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Oct 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000284007.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 385 of the MLH1 protein (p.Arg385His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 385 of the MLH1 protein (p.Arg385His). This variant is present in population databases (rs63750430, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 140759). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(May 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004236360.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Uncertain significance
(Feb 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000911263.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 385 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with histidine at codon 385 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with colorectal cancer (PMID: 35223509), an individual affected with Ewing sarcoma (PMID: 27498913), and individual affected with gastric cancer who also had a pathogenic variant in the ATM gene (PMID: 36627197), and in two unaffected individuals in a pancreatic case-control study (PMID: 32980694). This variant has been identified in 15/282582 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004840964.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces arginine with histidine at codon 385 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with histidine at codon 385 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with colorectal cancer (PMID: 35223509), an individual affected with Ewing sarcoma (PMID: 27498913), and individual affected with gastric cancer who also had a pathogenic variant in the ATM gene (PMID: 36627197), and in two unaffected individuals in a pancreatic case-control study (PMID: 32980694). This variant has been identified in 15/282582 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 7
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Uncertain significance
(Jul 01, 2019)
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no assertion criteria provided
Method: clinical testing
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Lynch-like syndrome
Affected status: yes
Allele origin:
somatic
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Constitutional Genetics Lab, Leon Berard Cancer Center
Accession: SCV001423878.1
First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Profiling of the genetic features of Chinese patients with gastric cancer with HRD germline mutations in a large-scale retrospective study. | Zhang C | Journal of medical genetics | 2023 | PMID: 36627197 |
Impact of Different Selection Approaches for Identifying Lynch Syndrome-Related Colorectal Cancer Patients: Unity Is Strength. | Fanale D | Frontiers in oncology | 2022 | PMID: 35223509 |
Genetic characterization of pancreatic cancer patients and prediction of carrier status of germline pathogenic variants in cancer-predisposing genes. | Mizukami K | EBioMedicine | 2020 | PMID: 32980694 |
Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity. | Li S | Journal of medical genetics | 2020 | PMID: 31391288 |
Germline DNA Repair Gene Mutation Landscape in Chinese Prostate Cancer Patients. | Wei Y | European urology | 2019 | PMID: 31248605 |
Germline mutation landscape of Chinese patients with familial breast/ovarian cancer in a panel of 22 susceptibility genes. | Wang J | Cancer medicine | 2019 | PMID: 30982232 |
Monogenic and polygenic determinants of sarcoma risk: an international genetic study. | Ballinger ML | The Lancet. Oncology | 2016 | PMID: 27498913 |
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
Text-mined citations for rs63750430 ...
HelpRecord last updated May 27, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.