Submissions for variant NM_002439.5(MSH3):c.2281G>T (p.Val761Leu)

gnomAD frequency: 0.00009  dbSNP: rs376555325

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804930	SCV000944868	uncertain significance	not provided	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 761 of the MSH3 protein (p.Val761Leu). This variant is present in population databases (rs376555325, gnomAD 0.03%). This missense change has been observed in individual(s) with MSH3-related conditions (PMID: 28944238). ClinVar contains an entry for this variant (Variation ID: 649891). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.
Ambry Genetics	RCV002442686	SCV002736258	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-22	criteria provided, single submitter	clinical testing	The p.V761L variant (also known as c.2281G>T), located in coding exon 16 of the MSH3 gene, results from a G to T substitution at nucleotide position 2281. The valine at codon 761 is replaced by leucine, an amino acid with highly similar properties. This alteration was identified in an individual diagnosed with colorectal cancer (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000804930	SCV003919526	uncertain significance	not provided	2022-10-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003461155	SCV004197121	uncertain significance	Endometrial carcinoma	2023-12-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000804930	SCV004221070	uncertain significance	not provided	2023-11-17	criteria provided, single submitter	clinical testing	The MSH3 c.2281G>T (p.Val761Leu) variant has been reported in the published literature in an individual with colorectal cancer (PMID: 28944238 (2017)). The frequency of this variant in the general population, 0.00028 (7/24784 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV004789204	SCV005402201	uncertain significance	Familial adenomatous polyposis 4	2024-06-10	criteria provided, single submitter	clinical testing	The MSH3 c.2281G>T (p.Val761Leu) missense change has a maximum subpopulation frequency of 0.03% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but this prediction has not been confirmed by functional studies. This variant has not been reported in individuals with MSH3-associated polyposis syndrome. 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.
Fulgent Genetics, Fulgent Genetics	RCV005036174	SCV005666201	uncertain significance	Endometrial carcinoma; Familial adenomatous polyposis 4	2024-05-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751719	SCV005360077	uncertain significance	MSH3-related disorder	2024-05-21	no assertion criteria provided	clinical testing	The MSH3 c.2281G>T variant is predicted to result in the amino acid substitution p.Val761Leu. This variant has been identified in one individual in a cohort study of over 1,200 colorectal cancer cases via targeted gene sequencing (Table S2. DeRycke et al 2017. PubMed ID: 28944238). This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD. This variant is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/649891/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.