Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000799438 | SCV000939100 | uncertain significance | not provided | 2025-02-03 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 593 of the MSH3 protein (p.Arg593Gln). This variant is present in population databases (rs764832633, gnomAD 0.009%). 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: 645380). 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 disruptive. 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 | RCV001013146 | SCV001173691 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-03-13 | criteria provided, single submitter | clinical testing | The p.R593Q variant (also known as c.1778G>A), located in coding exon 13 of the MSH3 gene, results from a G to A substitution at nucleotide position 1778. The arginine at codon 593 is replaced by glutamine, an amino acid with highly similar properties. This alteration was identified in a patient meeting testing criteria for HBOC (Chrysafi P et al. Cancers (Basel), 2023 Dec;15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. |
| Sema4, |
RCV001013146 | SCV002535984 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-09-16 | criteria provided, single submitter | curation | |
| Gene |
RCV000799438 | SCV002770029 | uncertain significance | not provided | 2024-10-31 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a patient with breast and colon cancer (PMID: 35475445); This variant is associated with the following publications: (PMID: 39049123, 35475445) |
| St. |
RCV003153840 | SCV003843117 | uncertain significance | Familial adenomatous polyposis 4 | 2022-10-17 | criteria provided, single submitter | clinical testing | The MSH3 c.1778G>A (p.Arg593Gln) missense change has a maximum subpopulation frequency of 0.0062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in at least one individual with colon cancer (PMID: 35475445). 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. |
| Baylor Genetics | RCV003461117 | SCV004197049 | uncertain significance | Endometrial carcinoma | 2024-02-01 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV005036159 | SCV005666192 | uncertain significance | Endometrial carcinoma; Familial adenomatous polyposis 4 | 2024-02-15 | criteria provided, single submitter | clinical testing |