ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.1144C>T (p.Arg382Cys)
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(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.1144C>T (p.Arg382Cys)
Variation ID: 232371 Accession: VCV000232371.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47429809 (GRCh38) [ NCBI UCSC ] 2: 47656948 (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 Oct 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.1144C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Arg382Cys missense NM_001258281.1:c.946C>T NP_001245210.1:p.Arg316Cys missense NC_000002.12:g.47429809C>T NC_000002.11:g.47656948C>T NG_007110.2:g.31686C>T LRG_218:g.31686C>T LRG_218t1:c.1144C>T LRG_218p1:p.Arg382Cys - Protein change
- R382C, R316C
- Other names
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- Canonical SPDI
- NC_000002.12:47429808:C:T
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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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
7315 | 7468 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 28, 2022 | RCV000214618.10 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jul 27, 2023 | RCV000480571.14 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jun 8, 2023 | RCV000409794.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 1, 2020 | RCV000761006.3 | |
Likely benign (1) |
criteria provided, single submitter
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Oct 8, 2023 | RCV000546544.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 11, 2023 | RCV003387810.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
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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
(Oct 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV000890921.2
First in ClinVar: Mar 19, 2019 Last updated: Dec 17, 2020 |
Comment:
The MSH2 c.1144C>T (p.Arg382Cys) missense change has a maximal subpopulation frequency of 0.0065% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/2-47656948-C-T). Seven of seven in silico algorithms predict … (more)
The MSH2 c.1144C>T (p.Arg382Cys) missense change has a maximal subpopulation frequency of 0.0065% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/2-47656948-C-T). Seven of seven in silico algorithms predict a deleterious effect on the gene or gene product (PP3), however these predictions have not been confirmed by functional studies. This variant has been reported in one individual with stomach adenocarcinoma (PMID: 29625052) and one individual with colorectal cancer (PMID: 25938944). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, PP3. (less)
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Uncertain significance
(May 31, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
inherited
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002025628.1 First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
Clinical Features:
Recurrent skin infections (present) , Recurrent otitis media (present) , Recurrent sinusitis (present) , Decreased circulating antibody level (present) , Acute promyelocytic leukemia (present) , … (more)
Recurrent skin infections (present) , Recurrent otitis media (present) , Recurrent sinusitis (present) , Decreased circulating antibody level (present) , Acute promyelocytic leukemia (present) , Hypotonia (present) , Pneumothorax (present) , Seizure (present) , Generalized joint hypermobility (present) , Delayed speech and language development (present) , Pilomatrixoma (present) (less)
Secondary finding: no
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Uncertain significance
(Nov 02, 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: SCV000489635.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Likely benign
(Mar 16, 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: SCV004018215.1
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
(Jul 27, 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: SCV000566392.6
First in ClinVar: Apr 29, 2017 Last updated: Aug 05, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in an individual with a personal and family history of colon cancer and polyps, in an individual with family history of breast/ovarian cancer, and in an individual with gastric cancer (Weren et al., 2015; Huang et al., 2018; Lerner-Ellis et al., 2021); Published functional studies suggest this variant has no damaging effect based on results of an assay measuring resistance to 6-TG (Jia et al., 2020); This variant is associated with the following publications: (PMID: 36451132, 29625052, 21120944, 18822302, 32885271, 25938944, 33357406) (less)
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Uncertain significance
(Sep 11, 2023)
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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: SCV004099692.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
Variant summary: MSH2 c.1144C>T (p.Arg382Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the … (more)
Variant summary: MSH2 c.1144C>T (p.Arg382Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) 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 3.2e-05 in 251454 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1144C>T has been reported in the literature in individuals affected with Breast/Ovarian cancer (Dorling_2021, Lerner-Ellis_2021), Colorectal Cancer (Weren_2015) and Stomach Cancer (Huang_2018). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. A cell-based assay using MSH2 deficient HAP1 cells suggest that the variant confers resistance to DNA damage induced by 6-thioguanine (Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 29625052, 25938944, 33471991, 32885271, 33357406). Eight ClinVar submitters have assessed the variant since 2014: six classified the variant as uncertain significance, and two as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Jun 08, 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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Baylor Genetics
Accession: SCV004194555.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Feb 02, 2022)
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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: SCV000689955.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with cysteine at codon 382 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with cysteine at codon 382 of the MSH2 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 reported in individuals affected with colonic adenomas (PMID: 25938944). This variant has been identified in 9/282852 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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Likely benign
(Oct 08, 2023)
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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: SCV000625229.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
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Uncertain significance
(Jun 28, 2022)
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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: SCV000276498.8
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.R382C variant (also known as c.1144C>T), located in coding exon 7 of the MSH2 gene, results from a C to T substitution at nucleotide … (more)
The p.R382C variant (also known as c.1144C>T), located in coding exon 7 of the MSH2 gene, results from a C to T substitution at nucleotide position 1144. The arginine at codon 382 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was identified in an individual with multiple colon polyps (Weren RD et al. Nat Genet, 2015 Jun;47:668-71). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This variant was also observed in 2/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550345.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MSH2 p.Arg382Cys variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, Zhejiang University Database, or the Mismatch … (more)
The MSH2 p.Arg382Cys variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, Zhejiang University Database, or the Mismatch Repair Genes Variant database. The variant was identified in dbSNP (ID: rs752373431) as "With Uncertain significance allele ", in ClinVar (classified as uncertain significance by Ambry Genetics, Counsyl, GeneDx, Invitae, Color Genomics), UMD-LSDB (1x as unclassified variant), and in Insight Hereditary Tumors database (1x). The variant was identified in control databases in 9 of 277218 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24032 chromosomes (freq: 0.00004), Other in 1 of 6466 chromosomes (freq: 0.0002), European in 4 of 126704 chromosomes (freq: 0.00003), East Asian in 1 of 18870 chromosomes (freq: 0.0001), and South Asian in 2 of 30782 chromosomes (freq: 0.0001); it was not observed in the Latino, Ashkenazi Jewish, and Finnish populations. The p.Arg382 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
Number of individuals with the variant: 1
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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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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 |
Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
Pathogenic Germline Variants in 10,389 Adult Cancers. | Huang KL | Cell | 2018 | PMID: 29625052 |
A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. | Weren RD | Nature genetics | 2015 | PMID: 25938944 |
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 rs752373431 ...
HelpRecord last updated May 01, 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.