Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV001013396 | SCV001173976 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-12-08 | criteria provided, single submitter | clinical testing | The p.R616C variant (also known as c.1846C>T), located in coding exon 13 of the MSH3 gene, results from a C to T substitution at nucleotide position 1846. The arginine at codon 616 is replaced by cysteine, an amino acid with highly dissimilar properties. 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 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. |
Labcorp Genetics |
RCV001038562 | SCV001202037 | uncertain significance | not provided | 2024-01-27 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 616 of the MSH3 protein (p.Arg616Cys). This variant is present in population databases (rs372874549, gnomAD 0.01%). 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: 820187). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine 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. |
Sema4, |
RCV001013396 | SCV002535996 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-09-16 | criteria provided, single submitter | curation | |
Gene |
RCV001038562 | SCV002601012 | uncertain significance | not provided | 2022-05-11 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); 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 | RCV003467608 | SCV004197003 | uncertain significance | Endometrial carcinoma | 2024-03-10 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001038562 | SCV005623798 | uncertain significance | not provided | 2024-11-29 | criteria provided, single submitter | clinical testing | The MSH3 c.1846C>T (p.Arg616Cys) variant has been reported in the published literature in an individual with no personal history of cancer (PMID: 29641532 (2018)). The frequency of this variant in the general population, 0.00012 (4/34586 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. |