Submissions for variant NM_000251.3(MSH2):c.2439G>A (p.Met813Ile)

gnomAD frequency: 0.00001  dbSNP: rs587781678

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129838	SCV000184654	likely benign	Hereditary cancer-predisposing syndrome	2019-03-12	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000168339	SCV000219028	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000482932	SCV000565202	uncertain significance	not provided	2022-04-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate variant results comparable to wild type: similar protein expression, cellular viability, induction of apoptosis, and response to DNA damaging drugs (Arora 2017); This variant is associated with the following publications: (PMID: 18822302, 21120944, 28494185)
Color Diagnostics, LLC DBA Color Health	RCV000129838	SCV000685044	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-14	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 813 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). A functional study has shown that this variant does not impact MSH2 protein function as determined by cell viability, caspase activation, and sensitivity to DNA-damaging agent (PMID: 28494185). 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 undergoing genetic screening for hereditary breast/ovarian cancer (PMID: 34359559), and has been reported in 3/60466 cases and 1/53461 unaffected controls in a large breast cancer case-control study (PMID: 33471991). This variant has been identified in 2/282712 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.
Sema4, Sema4	RCV000129838	SCV002534476	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-06	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003335115	SCV004043198	likely benign	Lynch syndrome 1	2023-08-17	criteria provided, single submitter	clinical testing	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: 27363726].
PreventionGenetics, part of Exact Sciences	RCV004532554	SCV004113723	uncertain significance	MSH2-related disorder	2023-02-16	criteria provided, single submitter	clinical testing	The MSH2 c.2439G>A variant is predicted to result in the amino acid substitution p.Met813Ile. This variant has been reported in one patient with breast cancer who also carried multiple variants of uncertain significance in other cancer genes (Lerner-Ellis et al. 2020. PubMed ID: 32885271). In vitro functional studies suggested that this variant is not expected to alter function (Arora et al. 2017. PubMed ID: 28494185). This variant is reported in 0.0028% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47705639-G-A). This variant is interpreted as likely benign and variant of uncertain significance in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141351). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV003997529	SCV004834194	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 813 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). A functional study has shown that this variant does not impact MSH2 protein function as determined by cell viability, caspase activation, and sensitivity to DNA-damaging agent (PMID: 28494185). 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 undergoing genetic screening for hereditary breast/ovarian cancer (PMID: 34359559), and has been reported in 3/60466 cases and 1/53461 unaffected controls in a large breast cancer case-control study (PMID: 33471991). This variant has been identified in 2/282712 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.