ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.820A>G (p.Ile274Val)
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(9); Benign(1); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.820A>G (p.Ile274Val)
Variation ID: 187433 Accession: VCV000187433.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47414296 (GRCh38) [ NCBI UCSC ] 2: 47641435 (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 Dec 19, 2017 May 1, 2024 Jan 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.820A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Ile274Val missense NM_000251.2(MSH2):c.820A>G NM_001258281.1:c.622A>G NP_001245210.1:p.Ile208Val missense NC_000002.12:g.47414296A>G NC_000002.11:g.47641435A>G NG_007110.2:g.16173A>G LRG_218:g.16173A>G LRG_218t1:c.820A>G LRG_218p1:p.Ile274Val - Protein change
- I274V, I208V
- Other names
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- Canonical SPDI
- NC_000002.12:47414295: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00006
The Genome Aggregation Database (gnomAD) 0.00008
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
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 |
7313 | 7466 |
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 18, 2023 | RCV000167160.11 | |
Benign (1) |
criteria provided, single submitter
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Jan 17, 2024 | RCV000198455.12 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Nov 25, 2018 | RCV000587804.8 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Aug 5, 2023 | RCV000663108.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 7, 2023 | RCV001248898.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 17, 2023 | RCV003995565.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 9, 2023 | RCV003416045.4 |
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
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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
(Mar 23, 2018)
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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: SCV000786225.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Likely benign
(Sep 06, 2018)
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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: SCV000292620.11
First in ClinVar: Jul 24, 2016 Last updated: Jul 24, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 26976419, 23047549)
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Uncertain significance
(Nov 25, 2018)
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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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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134376.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 01, 2022 |
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Uncertain significance
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Not Specified
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422581.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Ile274Val variant in MSH2 has been reported in 1 individual with primary epithelial ovarian cancer (PMID: 23047549), and as been identified in 0.02407% (6/24926) … (more)
The p.Ile274Val variant in MSH2 has been reported in 1 individual with primary epithelial ovarian cancer (PMID: 23047549), and as been identified in 0.02407% (6/24926) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs371944271). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as a VUS by 5 submitters (Variation ID: 187433). The Isoleucine (Ile) at position 274 is not highly conserved in mammals and evolutionary distant species, and 12 species (Shrew, Tetraodon, Fugu, Nile tilapia, Burton's mouthbreeder, Princess of Burundi, Zebra mbuna, Pundamilia nyererei, Medaka, Stickleback, Atlantic cod, and Lamprey) carry a Valine (Val), raising the possibility that this change at this position may be tolerated. However, other computational prediction tools do not provide strong support for or against an impact to the protein. One additional variant, resulting in a different amino acid change at the same position, p.Ile274Met, has been reported as a VUS in association with disease in ClinVar (Variation ID: 472815). In summary, the clinical significance of the p.Ile274Val variant is uncertain. ACMG/AMP Criteria applied: None (Richards 2015). (less)
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Uncertain significance
(Mar 11, 2022)
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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: SCV002526752.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MSH2 c.820A>G (p.I274V) variant has been reported in heterozygosity in at least one individual with epithelial ovarian cancer (PMID: 23047549). This variant was observed … (more)
The MSH2 c.820A>G (p.I274V) variant has been reported in heterozygosity in at least one individual with epithelial ovarian cancer (PMID: 23047549). This variant was observed in 6/24926 chromosomes in the African/African American population according to the Genome Aggregation Database (PMID: 32461654). The variant has been reported in ClinVar (Variation ID 187433). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Mar 07, 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: SCV000696288.3
First in ClinVar: Mar 17, 2018 Last updated: May 13, 2023 |
Comment:
Variant summary: MSH2 c.820A>G (p.Ile274Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the … (more)
Variant summary: MSH2 c.820A>G (p.Ile274Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.3e-05 in 150746 control chromosomes (gnomAD v3.1, genomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.820A>G has been reported in the literature in at-least one individual affected with epithelial ovarian cancer (Pal_2012). This report does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (MLH1 c.793C>T, p.Arg265Cys), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as VUS (n=5), Likely Benign (n=2) and Benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Likely benign
(Mar 17, 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: SCV004018253.1
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
(Mar 09, 2023)
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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: SCV004116251.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The MSH2 c.820A>G variant is predicted to result in the amino acid substitution p.Ile274Val. This variant has been identified in one individual with ovarian cancer … (more)
The MSH2 c.820A>G variant is predicted to result in the amino acid substitution p.Ile274Val. This variant has been identified in one individual with ovarian cancer (Supplementary Table 1 in Pal et al. 2012. PubMed ID: 23047549). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47641435-A-G) and is interpreted as a variant of uncertain significance by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/187433/). 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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Uncertain significance
(Aug 05, 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: SCV004196327.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Benign
(Jan 17, 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: SCV000254430.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
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Uncertain significance
(Jan 18, 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: SCV001343432.2
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces isoleucine with valine at codon 274 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces isoleucine with valine at codon 274 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with epithelial ovarian cancer (PMID: 23047549). This variant has been identified in 6/281746 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
(Sep 17, 2023)
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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: SCV004831477.1
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 isoleucine with valine at codon 274 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces isoleucine with valine at codon 274 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with epithelial ovarian cancer (PMID: 23047549). This variant has been identified in 6/281746 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: 6
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Likely benign
(May 30, 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: SCV000217991.7
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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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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Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. | Jia X | American journal of human genetics | 2021 | PMID: 33357406 |
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 |
Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. | Pal T | British journal of cancer | 2012 | PMID: 23047549 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/24c09552-9d8b-42ef-b1af-29325aacf958 | - | - | - | - |
Text-mined citations for rs371944271 ...
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.