Submissions for variant NM_000251.3(MSH2):c.174C>G (p.Phe58Leu)

dbSNP: rs372189599

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470314	SCV000548255	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-09-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491232	SCV000580391	likely benign	Hereditary cancer-predisposing syndrome	2021-11-24	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.
Color Diagnostics, LLC DBA Color Health	RCV000491232	SCV001342609	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 58 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).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 suspected of having Lynch syndrome (PMID: 25980754). This variant has been identified in 3/233138 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.
Sema4, Sema4	RCV000491232	SCV002534406	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-11	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003153620	SCV003843019	uncertain significance	Lynch syndrome 1	2023-01-27	criteria provided, single submitter	clinical testing	The MSH2 c.174C>G (p.Phe58Leu) missense change has a maximum subpopulation frequency of 0.0090% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in the literature in at least one individual with suspected Lynch syndrome (PMID: 25980754). To our knowledge, this variant has not been reported in individual(s) with constitutional mismatch repair deficiency. 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.
GeneDx	RCV003329284	SCV004036854	uncertain significance	not provided	2023-09-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on 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); This variant is associated with the following publications: (PMID: 18822302, 21120944, 33471991, 33357406, 25980754)
Baylor Genetics	RCV003153620	SCV004196298	uncertain significance	Lynch syndrome 1	2023-08-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004806312	SCV005427931	uncertain significance	Lynch syndrome	2024-03-04	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 58 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 been reported in individuals suspected of having Lynch syndrome (PMID: 25980754) or affected with lung cancer (Wang et al. 2018, Poster P2.03-08). This variant has been identified in 3/233138 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003329284	SCV005623630	uncertain significance	not provided	2024-11-13	criteria provided, single submitter	clinical testing	The MSH2 c.174C>G (p.Phe58Leu) variant has been reported in the published literature in individuals with Lynch syndrome (PMID: 25980754 (2015)) and breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). A screening assay based on cell survival in response to 6-thioguanine treatment indicates this variant does not have a deleterious effect on DNA mismatch repair function (PMID: 33357406 (2021)). The frequency of this variant in the general population, 0.00009 (3/33408 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Myriad Genetics, Inc.	RCV003153620	SCV005897319	likely benign	Lynch syndrome 1	2024-12-03	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV004806312	SCV005921072	uncertain significance	Lynch syndrome	2021-03-19	criteria provided, single submitter	clinical testing