Submissions for variant NM_000251.3(MSH2):c.2260A>T (p.Thr754Ser)

dbSNP: rs757268664

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221755	SCV000273102	likely benign	Hereditary cancer-predisposing syndrome	2022-09-27	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	RCV000464199	SCV000548248	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 754 of the MSH2 protein (p.Thr754Ser). This variant is present in population databases (rs757268664, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 229770). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000221755	SCV000903534	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 754 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251408 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780438	SCV000917687	uncertain significance	not specified	2018-01-26	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.2260A>T (p.Thr754Ser) variant involves the alteration of a conserved nucleotide that leads to a missense change in the DNA mismatch repair protein MutS, C-terminal domain that is comprised of the ATPase domain and the HTH (helix-turn-helix) domain, the latter being involved in dimer contacts (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index), however these predictions have not been confirmed by published functional studies. This variant was found in 2/246192 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). The variant of interest has not, to our knowledge, been reported in affected individuals via publications,` nor evaluated for functional impact by in vivo/vitro studies. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
GeneDx	RCV001843496	SCV002102667	uncertain significance	not provided	2023-07-24	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 demonstrate 6-thioguanine resistance similar to wildtype, suggesting no impact on mismatch repair activity (PMID: 33357406); This variant is associated with the following publications: (PMID: 30989050, 21120944, 18822302, 33357406)
Fulgent Genetics, Fulgent Genetics	RCV002485413	SCV002779431	uncertain significance	Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2	2021-07-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001843496	SCV004220983	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000008 (2/251408 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. To the best of our knowledge, this variant has not been reported in individuals with an MSH2 related condition. However, a functional analysis study has reported that this variant is functionally neutral (PMID: 33357406 (2021)). Additional studies are required to determine the global effect of this variant on MSH2 protein function. 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.
All of Us Research Program, National Institutes of Health	RCV003997767	SCV004825814	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 754 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251408 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.
Myriad Genetics, Inc.	RCV004020644	SCV004931803	likely benign	Lynch syndrome 1	2024-03-26	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].