Submissions for variant NM_000251.3(MSH2):c.183G>C (p.Gln61His)

dbSNP: rs751082926

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000571464	SCV000669845	likely benign	Hereditary cancer-predisposing syndrome	2022-08-01	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.
PreventionGenetics, part of Exact Sciences	RCV000679297	SCV000806013	uncertain significance	not provided	2017-02-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000571464	SCV001342610	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-26	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 61 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/232262 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.
GeneDx	RCV000679297	SCV001795166	uncertain significance	not provided	2020-07-07	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27601186, 25395895, 22949387)
Invitae	RCV001858303	SCV002162365	benign	Hereditary nonpolyposis colorectal neoplasms	2023-08-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001042	SCV004831994	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 61 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/232262 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.