Submissions for variant NM_002439.5(MSH3):c.2044G>C (p.Val682Leu)

gnomAD frequency: 0.00012  dbSNP: rs145657887

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000817584	SCV000958153	uncertain significance	not provided	2025-01-17	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 682 of the MSH3 protein (p.Val682Leu). This variant is present in population databases (rs145657887, gnomAD 0.03%). This missense change has been observed in individual(s) with colon cancer (PMID: 29212164). ClinVar contains an entry for this variant (Variation ID: 660399). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	RCV001014172	SCV001174854	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-08	criteria provided, single submitter	clinical testing	The p.V682L variant (also known as c.2044G>C), located in coding exon 14 of the MSH3 gene, results from a G to C substitution at nucleotide position 2044. The valine at codon 682 is replaced by leucine, an amino acid with highly similar properties. This variant has been observed in a Caucasian female diagnosed with microsatellite stable (MSS) rectal cancer at age 59y and polyps whose family history meets Amsterdam criteria (Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463). This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Sema4, Sema4	RCV001014172	SCV002536029	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-16	criteria provided, single submitter	curation
GeneDx	RCV000817584	SCV002758902	uncertain significance	not provided	2022-05-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with colorectal cancer in the published literature (Raskin 2017); This variant is associated with the following publications: (PMID: 29212164)
Baylor Genetics	RCV003467482	SCV004197019	uncertain significance	Endometrial carcinoma	2024-03-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000817584	SCV004221061	uncertain significance	not provided	2024-02-24	criteria provided, single submitter	clinical testing	The MSH3 c.2044G>C (p.Val682Leu) variant has been reported in the published literature in individuals with colorectal cancer (PMID: 29212164 (2017)) and melanoma and rectal cancer (PMID: 29641532 (2018)). This variant has also been identified in a prostate cancer tumor specimen (PMID: 31874108 (2020)). The frequency of this variant in the general population, 0.00042 (11/26126 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004596356	SCV005090648	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV004576973	SCV001749504	not provided	Familial adenomatous polyposis 4		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 03-11-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004751735	SCV005348986	uncertain significance	MSH3-related disorder	2024-08-13	no assertion criteria provided	clinical testing	The MSH3 c.2044G>C variant is predicted to result in the amino acid substitution p.Val682Leu. This variant was reported with uncertain significance in an individual with colorectal cancer (Supplemental Tables 1 and 2, Raskin et al. 2017. PubMed ID: 29212164). This variant is reported in 0.035% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is reported as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/660399/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.