Submissions for variant NM_002439.5(MSH3):c.421T>C (p.Cys141Arg)

gnomAD frequency: 0.00023  dbSNP: rs143733332

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000820495	SCV000961211	uncertain significance	not provided	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 141 of the MSH3 protein (p.Cys141Arg). This variant is present in population databases (rs143733332, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with MSH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 662768). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Ambry Genetics	RCV001022079	SCV001183772	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-18	criteria provided, single submitter	clinical testing	The p.C141R variant (also known as c.421T>C), located in coding exon 3 of the MSH3 gene, results from a T to C substitution at nucleotide position 421. The cysteine at codon 141 is replaced by arginine, an amino acid with highly dissimilar properties. 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	RCV001022079	SCV002536525	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-18	criteria provided, single submitter	curation
Baylor Genetics	RCV003461266	SCV004196948	uncertain significance	Endometrial carcinoma	2024-03-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000820495	SCV004221106	uncertain significance	not provided	2024-08-13	criteria provided, single submitter	clinical testing	The MSH3 c.421T>C (p.Cys141Arg) variant has not been reported as a germline variant in individuals with MSH3-related conditions in the published literature. The frequency of this variant in the general population, 0.001 (26/24942 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV000820495	SCV005331814	uncertain significance	not provided	2023-11-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with breast cancer who also harbored a pathogenic PALB2 variant (Masanam et al., 2022); This variant is associated with the following publications: (PMID: Masanam2022)
Fulgent Genetics, Fulgent Genetics	RCV005036214	SCV005673164	uncertain significance	Endometrial carcinoma; Familial adenomatous polyposis 4	2024-06-17	criteria provided, single submitter	clinical testing