Submissions for variant NM_000251.3(MSH2):c.1530G>C (p.Gln510His)

gnomAD frequency: 0.00004  dbSNP: rs587782355

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235175	SCV000211186	uncertain significance	not provided	2023-07-14	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 suggest a neutral effect: demonstrates sensitivity to 6-TG and mismatch repair (MMR) function similar to wild-type (Jia et al., 2020); Observed in individuals with endometrial cancer (Ring et al., 2016); This variant is associated with the following publications: (PMID: 18822302, 21120944, 9774676, 33357406, 27443514)
Ambry Genetics	RCV000160591	SCV000214490	likely benign	Hereditary cancer-predisposing syndrome	2022-01-26	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	RCV000548522	SCV000625279	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160591	SCV000911171	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 510 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 endometrial cancer (PMID: 27443514). This variant has been identified in 3/282744 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.
Illumina Laboratory Services, Illumina	RCV001137232	SCV001297152	uncertain significance	Lynch syndrome 1	2018-01-12	criteria provided, single submitter	clinical testing	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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001137232	SCV003843033	uncertain significance	Lynch syndrome 1	2023-02-09	criteria provided, single submitter	clinical testing	The MSH2 c.1530G>C (p.Gln510His) missense change has a maximum subpopulation frequency of 0.0023% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about the effect on protein function, however a functional assay using a massively parallel screen in human cells indicated that this variant is neutral (PMID: 33357406). This variant has been reported in the literature in an individual with endometrial carcinoma (PMID: 27443514). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Myriad Genetics, Inc.	RCV001137232	SCV004018623	likely benign	Lynch syndrome 1	2023-11-14	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].
Baylor Genetics	RCV001137232	SCV004196293	uncertain significance	Lynch syndrome 1	2023-08-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544469	SCV004759076	uncertain significance	MSH2-related disorder	2024-02-12	criteria provided, single submitter	clinical testing	The MSH2 c.1530G>C variant is predicted to result in the amino acid substitution p.Gln510His. This variant has been reported in one patient with endometrial cancer (Ring et al. 2016. PubMed ID: 27443514). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as likely benign or uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182563/). 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	RCV003998473	SCV004833520	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 510 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 endometrial cancer (PMID: 27443514). This variant has been identified in 3/282744 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.