ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.128A>G (p.Tyr43Cys)
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(8); Likely benign(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.128A>G (p.Tyr43Cys)
Variation ID: 90619 Accession: VCV000090619.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47403319 (GRCh38) [ NCBI UCSC ] 2: 47630458 (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 Mar 24, 2015 May 1, 2024 Feb 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.128A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Tyr43Cys missense NM_001258281.1:c.-30-41A>G intron variant NC_000002.12:g.47403319A>G NC_000002.11:g.47630458A>G NG_007110.2:g.5196A>G LRG_218:g.5196A>G LRG_218t1:c.128A>G LRG_218p1:p.Tyr43Cys P43246:p.Tyr43Cys - Protein change
- Y43C
- Other names
- p.Y43C:TAT>TGT
- Canonical SPDI
- NC_000002.12:47403318:A:G
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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.
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00011
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
Help
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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MSH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7314 | 7467 |
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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Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Jun 21, 2021 | RCV000131211.15 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Sep 22, 2022 | RCV000212578.10 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Mar 23, 2023 | RCV000409784.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000764419.2 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 28, 2024 | RCV000524339.11 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 9, 2023 | RCV000656872.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 1, 2019 | RCV001262887.1 | |
MSH2-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Feb 13, 2024 | RCV004537289.1 |
not provided (1) |
no classification provided
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- | RCV003330424.1 |
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
(Mar 31, 2016)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000539687.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 2 papers in HGMD; ExAC: 2/41748 European; ClinVar: 3 VUS (1 expert panel) (less)
Method: Genome/Exome Filtration
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Uncertain significance
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Sarcoma,
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440923.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Uncertain significance
(Feb 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001482848.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Likely benign
(Jun 21, 2021)
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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: SCV000537603.6
First in ClinVar: Sep 24, 2016 Last updated: Jan 08, 2022 |
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Likely benign
(Sep 22, 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: SCV000919683.2
First in ClinVar: Jun 03, 2019 Last updated: Nov 05, 2022 |
Comment:
Variant summary: MSH2 c.128A>G (p.Tyr43Cys) results in a non-conservative amino acid change located in the N-terminal domain (IPR007695) of the encoded protein sequence. Five of … (more)
Variant summary: MSH2 c.128A>G (p.Tyr43Cys) results in a non-conservative amino acid change located in the N-terminal domain (IPR007695) of 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 7.3e-05 in 261262 control chromosomes, exclusively reported within the Non-Finnish European subpopulation at a frequency of 0.00016 in the gnomAD database. This frequency is not higher than the estimated expected maximum for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (0.00057), allowing no conclusion about variant significance. The variant, c.128A>G, has been reported in the literature in individuals affected with colorectal cancer / (suspected) Lynch syndrome and with other tumor phenotypes, which were mostly outside of the Lynch syndrome tumor spectrum (e.g. Schmitt_2002, Auclair_2006, Aloraifi_2015, Zhang_2015, Chan_2018, Dominguez-Valentin_2018, Sehdev_2018, Li_2020, Dorling_2021), but was also found in several healthy controls (e.g. Dorling_2021). Co-occurrences with other pathogenic variant(s) have been reported (MSH6 c.2405del, p.802LeufsX7 in the UMD database), providing supporting evidence for a benign role. Multiple publications reported experimental evidence evaluating an impact on protein function, and all of them demonstrated no damaging effect for this variant (Auclair_2006, Bouvet_2019, Jia_2021). Eleven other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (n=7) or likely benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Mar 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004018416.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic … (more)
This variant is considered likely 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]. (less)
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Uncertain significance
(Jan 09, 2023)
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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: SCV001469550.3
First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.00016 (19/118526 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.00016 (19/118526 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 35264596 (2022), 31569399 (2019), 30093976 (2018), 29458332 (2018), 26094658 (2015)), pancreatic cancer (PMID: 30131383 (2018)), and colorectal cancer (PMID: 22290698 (2012)). It has been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). Functional studies have shown that this variant does not result in aberrant splicing (PMID: 16395668 (2006)) and does not have a deleterious effect on MSH2 methylation and mismatch repair functions (PMIDs: 30998989 (2019) and 33357406 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Feb 13, 2024)
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criteria provided, single submitter
Method: clinical testing
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MSH2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004121669.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
The MSH2 c.128A>G variant is predicted to result in the amino acid substitution p.Tyr43Cys. This variant has been reported in patients with hereditary nonpolyposis colon … (more)
The MSH2 c.128A>G variant is predicted to result in the amino acid substitution p.Tyr43Cys. This variant has been reported in patients with hereditary nonpolyposis colon cancer, breast cancer, colorectal cancer and leukemia (Auclair et al. 2006. PubMed ID: 16395668; Aloraifi et al. 2015. PubMed ID: 26094658; Dominguez-Valentin et al. 2018. PubMed ID: 29458332; Zhang et al. 2015. PubMed ID: 26580448). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://0-www-ncbi-nlm-nih-gov.brum.beds.ac.uk/clinvar/variation/90619). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Likely benign
(Feb 05, 2019)
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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: SCV000186161.9
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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Lynch syndrome 1
Muir-Torré syndrome Mismatch repair cancer syndrome 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000895476.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001135690.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
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Uncertain significance
(May 04, 2016)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000488599.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Likely benign
(Sep 10, 2020)
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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: SCV000211203.16
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 26094658, 16395668, 21153778, 31569399, 22290698, 18383312, 19389263, 26333163, 25925381, 26580448, 22144684, 29458332, 29596542, 30131383, 30998989, 30093976)
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Likely benign
(Jan 28, 2024)
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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: SCV000254380.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Lynch syndrome
Muir-Torré syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV004037561.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant classified as Likely benign and reported on 02-15-2021 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more)
Variant classified as Likely benign and reported on 02-15-2021 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Breast carcinoma (present) , Family history of cancer (present)
Indication for testing: Diagnostic
Age: 60-69 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2021-02-15
Testing laboratory interpretation: Likely benign
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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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Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. | Guindalini RSC | Scientific reports | 2022 | PMID: 35264596 |
The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. | Jia X | American journal of human genetics | 2021 | PMID: 33357406 |
Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity. | Li S | Journal of medical genetics | 2020 | PMID: 31391288 |
Novel Genetic Markers for Early Detection of Elevated Breast Cancer Risk in Women. | Wu B | International journal of molecular sciences | 2019 | PMID: 31569399 |
Methylation Tolerance-Based Functional Assay to Assess Variants of Unknown Significance in the MLH1 and MSH2 Genes and Identify Patients With Lynch Syndrome. | Bouvet D | Gastroenterology | 2019 | PMID: 30998989 |
Germline and Somatic DNA Damage Repair Gene Mutations and Overall Survival in Metastatic Pancreatic Adenocarcinoma Patients Treated with FOLFIRINOX. | Sehdev A | Clinical cancer research : an official journal of the American Association for Cancer Research | 2018 | PMID: 30131383 |
Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers. | Chan GHJ | Oncotarget | 2018 | PMID: 30093976 |
Identification of genetic variants for clinical management of familial colorectal tumors. | Dominguez-Valentin M | BMC medical genetics | 2018 | PMID: 29458332 |
Germline Mutations in Predisposition Genes in Pediatric Cancer. | Zhang J | The New England journal of medicine | 2015 | PMID: 26580448 |
Protein-truncating variants in moderate-risk breast cancer susceptibility genes: a meta-analysis of high-risk case-control screening studies. | Aloraifi F | Cancer genetics | 2015 | PMID: 26250988 |
Detection of novel germline mutations for breast cancer in non-BRCA1/2 families. | Aloraifi F | The FEBS journal | 2015 | PMID: 26094658 |
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 |
Classification of mismatch repair gene missense variants with PON-MMR. | Ali H | Human mutation | 2012 | PMID: 22290698 |
Investigation on the role of nsSNPs in HNPCC genes--a bioinformatics approach. | Doss CG | Journal of biomedical science | 2009 | PMID: 19389263 |
Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). | Chao EC | Human mutation | 2008 | PMID: 18383312 |
Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing. | Auclair J | Human mutation | 2006 | PMID: 16395668 |
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Text-mined citations for rs17217723 ...
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.