Submissions for variant NM_000251.3(MSH2):c.439G>A (p.Val147Ile)

gnomAD frequency: 0.00001  dbSNP: rs773125415

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458857	SCV000548139	benign	Hereditary nonpolyposis colorectal neoplasms	2024-11-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000568213	SCV000669750	likely benign	Hereditary cancer-predisposing syndrome	2023-11-20	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759835	SCV000889440	uncertain significance	not provided	2024-11-04	criteria provided, single submitter	clinical testing	The MSH2 c.439G>A (p.Val147Ile) variant has been reported in the published literature in an individual with ovarian cancer (PMID: 36531003 (2022)). It has also been reported in both reportedly healthy individuals and individuals with breast cancer in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/)). An experimental study on human cells suggest this variant has a neutral impact on protein function, however further evidence is needed to assess the global impact of this variant (PMID: 33357406 (2021)). The frequency of this variant in the general population, 0.000026 (3/113732 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000568213	SCV000903295	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 147 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) . This variant has reported in an individual affected with ovarian cancer (PMID: 33357406). This variant has been identified in 3/251448 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	RCV000759835	SCV004170482	uncertain significance	not provided	2023-10-18	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; Observed in an individual with high-grade serous carcinoma in published literature (Andrikopoulou et al., 2022); 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); This variant is associated with the following publications: (PMID: 18822302, 21120944, 36531003, 33357406)
Myriad Genetics, Inc.	RCV003449128	SCV004186070	likely benign	Lynch syndrome 1	2023-11-22	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].
All of Us Research Program, National Institutes of Health	RCV004000775	SCV004830288	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 147 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) . This variant has reported in an individual affected with ovarian cancer (PMID: 33357406). This variant has been identified in 3/251448 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000568213	SCV005688853	uncertain significance	Hereditary cancer-predisposing syndrome	2025-01-30	criteria provided, single submitter	clinical testing	The missense variant NM_000251.3(MSH2):c.439G>A (p.Val147Ile) has not been reported previously as a pathogenic variant, to our knowledge. There is a small physicochemical difference between valine and isoleucine, which is not likely to impact secondary protein structure as these residues share similar properties. 3 variants within 6 amino acid positions of the variant p.Val147Ile have been shown to be pathogenic, while only 2 have been shown to be benign. There are no benign variants within 3 amino acid positions of the variant p.Val147Ile. For these reasons, this variant has been classified as Uncertain Significance