Submissions for variant NM_000251.3(MSH2):c.1413A>C (p.Lys471Asn)

dbSNP: rs745874745

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166506	SCV000217305	likely benign	Hereditary cancer-predisposing syndrome	2021-10-29	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	RCV000166506	SCV000684937	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 471 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/251306 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.
Invitae	RCV000629905	SCV000750861	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-05-09	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 471 of the MSH2 protein (p.Lys471Asn). This variant is present in population databases (rs745874745, 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: 186853). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is not expected to disrupt MSH2 protein 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477630	SCV004220948	uncertain significance	not provided	2023-07-27	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with colorectal cancer, who also had a frameshift MLH1 variant (PMID: 37088804 (2023)). The frequency of this variant in the general population, 0.0000088 (1/113608 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.
All of Us Research Program, National Institutes of Health	RCV003995508	SCV004833319	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 471 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/251306 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003477630	SCV004848773	uncertain significance	not provided	2022-08-31	criteria provided, single submitter	clinical testing	The p.Lys471Asn variant in MSH2 has not been previously reported in individuals with colorectal cancer but has been identified in 0.0009% (1/113608) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 186853). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355772	SCV001550747	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Lys471Asn variant was not identified in the literature. The variant was identified in dbSNP (ID: rs745874745) as "With Likely benign, Uncertain significance allele", in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and Color), and in UMD-LSDB (2x as unclassified variant). The variant was identified in control databases in 2 of 246082 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 2 of 111552 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Lys471 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.