Submissions for variant NM_000251.3(MSH2):c.1825G>T (p.Ala609Ser)

gnomAD frequency: 0.00001  dbSNP: rs150980616

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223424	SCV000273426	likely benign	Hereditary cancer-predisposing syndrome	2021-12-08	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	RCV000477055	SCV000548144	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765670	SCV000897012	uncertain significance	Lynch syndrome 1; Mismatch repair cancer syndrome 1; Muir-Torré syndrome	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001550360	SCV001770674	uncertain significance	not provided	2019-10-18	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with cancer (Li 2019); This variant is associated with the following publications: (PMID: 31391288, 22712459)
Color Diagnostics, LLC DBA Color Health	RCV000223424	SCV002053527	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 609 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251474 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.
PreventionGenetics, part of Exact Sciences	RCV004532776	SCV004121293	uncertain significance	MSH2-related disorder	2022-11-16	criteria provided, single submitter	clinical testing	The MSH2 c.1825G>T variant is predicted to result in the amino acid substitution p.Ala609Ser. This variant has been reported in an individual with cancer (Table S5, Li et al. 2020. PubMed ID: 31391288). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47702229-G-T), and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/230023/). A different substitution affecting the same amino acid (p.Ala609Val) has been reported in patients with Extramammary Paget disease (Kang et al. 2016. PubMed ID: 27487738; Supplemetary eTable2, Jiang et al. 2019. PubMed ID: 30521064). 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	RCV003997795	SCV004829685	uncertain significance	Lynch syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 609 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251474 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.