Submissions for variant NM_000251.3(MSH2):c.440T>G (p.Val147Gly)

gnomAD frequency: 0.00001  dbSNP: rs760851623

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588981	SCV000569918	uncertain significance	not provided	2018-10-29	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.440T>G at the cDNA level, p.Val147Gly (V147G) at the protein level, and results in the change of a Valine to a Glycine (GTT>GGT). This variant was observed in a cohort of breast cancer patients, unselected for family history (Tung 2016). MSH2 Val147Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the connector domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Val147Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588981	SCV000696269	uncertain significance	not provided	2017-03-14	criteria provided, single submitter	clinical testing	Variant summary: The c.440T>G (p.Val147Gly) in MSH2 gene is a missense change that involves a non-conserved nucleotide and 3/5 in silico tools predict deleterious outcome. The variant of interest is located outside of any known functional domain or repeats, however no studies determining the functional impact of this variant have been conducted and published at the time of evaluation. The variant is present in the large control population dataset of ExAC at a frequency 0.000016 (2/121412 chrs tested), which does not exceed the maximal expected frequency of a pathogenic allele (0.00057) in this gene. The variant is variant has been reported in 1 BrC patient without strong evidence for causality. The c.440T>G has not been cited by a reputable database/clinical laboratory. Taking together, the variant was classified as VUS.
Color Diagnostics, LLC DBA Color Health	RCV000771216	SCV000903296	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glycine at codon 147 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 breast cancer (PMID: 26976419). This variant has been identified in 2/251436 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.
Ambry Genetics	RCV000771216	SCV001184179	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	clinical testing	The p.V147G variant (also known as c.440T>G), located in coding exon 3 of the MSH2 gene, results from a T to G substitution at nucleotide position 440. The valine at codon 147 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J Clin Oncol, 2016 May;34:1460-8). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV001051880	SCV001216062	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-09-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535515	SCV004119314	uncertain significance	MSH2-related disorder	2023-05-16	criteria provided, single submitter	clinical testing	The MSH2 c.440T>G variant is predicted to result in the amino acid substitution p.Val147Gly. This variant was reported as a variant of uncertain significance in a cohort of individuals with breast cancer (Table A2 in Tung et al 2016. PubMed ID: 26976419). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47637306-T-G) and is reported in ClinVar as likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/420893/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588981	SCV004565257	uncertain significance	not provided	2023-03-09	criteria provided, single submitter	clinical testing	The MSH2 c.440T>G; p.Val147Gly variant (rs760851623) is reported in the literature in one individual affected with breast cancer (Tung 2016). This variant is also reported in ClinVar (Variation ID: 420893). This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. A massively parallel cell based functional assay with susceptibility to DNA damaging agent, 6-thioguanine (6-TG), suggests the functionality of this variant to be neutral (Jia 2021). However, computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.645). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Jia X et al. Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. Am J Hum Genet. 2021 Jan 7;108(1):163-175. PMID: 33357406. Tung N et al. Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. J Clin Oncol. 2016 May 1;34(13):1460-8. PMID: 26976419.
All of Us Research Program, National Institutes of Health	RCV004003339	SCV004830299	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glycine at codon 147 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26976419). This variant has been identified in 2/251436 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.