ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.55T>C (p.Phe19Leu)
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(3); Benign(3); Likely benign(8)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.55T>C (p.Phe19Leu)
Variation ID: 182595 Accession: VCV000182595.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47403246 (GRCh38) [ NCBI UCSC ] 2: 47630385 (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 Oct 8, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.55T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Phe19Leu missense NM_001258281.1:c.-31+71T>C intron variant NC_000002.12:g.47403246T>C NC_000002.11:g.47630385T>C NG_007110.2:g.5123T>C LRG_218:g.5123T>C LRG_218t1:c.55T>C LRG_218p1:p.Phe19Leu - Protein change
- F19L
- Other names
- p.F19L:TTC>CTC
- Canonical SPDI
- NC_000002.12:47403245:T:C
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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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0.00060 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00011
Exome Aggregation Consortium (ExAC) 0.00035
1000 Genomes Project 30x 0.00047
1000 Genomes Project 0.00060
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00062
Trans-Omics for Precision Medicine (TOPMed) 0.00062
The Genome Aggregation Database (gnomAD) 0.00063
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 |
7401 | 7563 |
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 (3) |
criteria provided, multiple submitters, no conflicts
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Jan 2, 2022 | RCV000160635.19 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Mar 20, 2023 | RCV000409531.17 | |
Likely benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV001084278.16 | |
Likely benign (1) |
criteria provided, conflicting classifications
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Apr 27, 2021 | RCV000588459.25 | |
Benign (1) |
criteria provided, single submitter
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Aug 22, 2023 | RCV003323295.8 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Aug 28, 2023 | RCV001255213.16 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 12, 2023 | RCV003492654.1 | |
MSH2-related disorder
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Likely benign (1) |
no assertion criteria provided
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Feb 11, 2022 | RCV004528902.2 |
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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Likely benign
(Apr 27, 2021)
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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: SCV000211236.15
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 25503501, 22949387, 25256751)
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Uncertain significance
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001302261.1
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
(Oct 25, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002066532.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.55T>C, in exon 1 that results in an amino acid change, p.Phe19Leu. This sequence … (more)
DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.55T>C, in exon 1 that results in an amino acid change, p.Phe19Leu. This sequence change does not appear to have been previously described in individuals with MSH2-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.20% in the African subpopulation (dbSNP rs141711342). The p.Phe19Leu change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Phe19Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Phe19Leu change remains unknown at this time. (less)
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Uncertain significance
(Dec 18, 2015)
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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: SCV000488058.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Benign
(Mar 15, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601485.4
First in ClinVar: Sep 28, 2017 Last updated: Dec 31, 2022 |
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Likely benign
(Aug 28, 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: SCV000696277.4
First in ClinVar: Mar 17, 2018 Last updated: Oct 04, 2023 |
Comment:
Variant summary: MSH2 c.55T>C (p.Phe19Leu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain (IPR007695) of the … (more)
Variant summary: MSH2 c.55T>C (p.Phe19Leu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, 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 0.00011 in 219030 control chromosomes, predominantly at a frequency of 0.0018 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.55T>C has been reported in the literature in individuals affected with Colorectal Cancer (e.g. Thompson_2013) and breast cancer (e.g. Maxwell_2014) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variant(s) have been reported (MLH1 c.1624C>T, p.Gln542X), providing supporting evidence for a benign role. At least one publication reports the variant as non-pathogenic based on a genetic screen that assesses the MMR-abrogating effect of endogenously expressed Msh2 variants in mESCs (example, Houlleberghs_2016). The following publications have been ascertained in the context of this evaluation (PMID: 22949387, 25503501, 26951660, 30998989). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=5) and benign/likely benign (n=8). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Jan 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004239288.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Likely benign
(Nov 01, 2018)
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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: SCV000214558.8
First in ClinVar: Mar 24, 2015 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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Likely benign
(Apr 27, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002534534.1
First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020 |
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Likely benign
(Mar 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV002570278.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
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Benign
(Mar 20, 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: SCV004018299.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features … (more)
This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. 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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Benign
(Aug 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colon cancer
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV000837810.3
First in ClinVar: Oct 10, 2018 Last updated: Aug 25, 2023 |
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Likely benign
(Jan 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: SCV000910843.2
First in ClinVar: May 19, 2019 Last updated: Feb 14, 2024 |
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Likely benign
(Feb 01, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000218919.12
First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024 |
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Likely benign
(Feb 11, 2022)
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no assertion criteria provided
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: SCV000806045.3
First in ClinVar: Sep 13, 2018 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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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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Identification of SNPs in hMSH3/MSH6 interaction domain affecting the structure and function of MSH2 protein. | Singh S | Biotechnology and applied biochemistry | 2022 | PMID: 34837403 |
Lynch Syndrome. | Adam MP | - | 2021 | PMID: 20301390 |
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 |
Oligonucleotide-directed mutagenesis screen to identify pathogenic Lynch syndrome-associated MSH2 DNA mismatch repair gene variants. | Houlleberghs H | Proceedings of the National Academy of Sciences of the United States of America | 2016 | PMID: 26951660 |
Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. | Maxwell KN | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25503501 |
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 |
Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions. | Thompson BA | Human mutation | 2013 | PMID: 22949387 |
Text-mined citations for rs141711342 ...
HelpRecord last updated Oct 13, 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.