Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000570527 | SCV000669971 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-21 | criteria provided, single submitter | clinical testing | The p.A494V variant (also known as c.1481C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1481. The alanine at codon 494 is replaced by valine, an amino acid with similar properties. This alteration has been detected in a cohort of 1893 women with epithelial ovarian cancer from three population-based studies who were ascertained for mutations in MLH1, MSH2 and MSH6 (Pal T et al. Br. J. Cancer, 2012 Nov;107:1783-90), in 1/711 Russian hereditary breast cancer patients (Nikitin AG et al. Front Oncol, 2020 May;10:666), in 1/125 early-onset colorectal cancer patients from Kazakhstan (Zhunussova G et al. Front Oncol, 2019 Aug;9:673), and in 1/464 individuals from familial pancreatic cancer families (Abe T et al. J Clin Oncol, 2019 05;37:1070-1080). This amino acid position is highly 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. |
| Color Diagnostics, |
RCV000570527 | SCV000909049 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-02-08 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with valine at codon 494 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 23047549). This variant has been identified in 1/251176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Labcorp Genetics |
RCV000816280 | SCV000956781 | likely benign | Hereditary nonpolyposis colorectal neoplasms | 2023-11-27 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV004530607 | SCV004119190 | uncertain significance | MSH6-related disorder | 2023-08-14 | criteria provided, single submitter | clinical testing | The MSH6 c.1481C>T variant is predicted to result in the amino acid substitution p.Ala494Val. This variant has been reported in several cohort studies about ovarian cancer, colorectal cancer, pancreatic cancer and breast cancer (Pal et al. 2012. PubMed ID: 23047549. Table S1; Zhunussova et al. 2019. PubMed ID: 31428572. Table S6; Abe et al. 2019. PubMed ID: 30883245; Nikitin et al. 2020. PubMed ID: 32547938. Table S2). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48026603-C-T) and interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/483792/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
| Baylor Genetics | RCV003465239 | SCV004195774 | uncertain significance | Endometrial carcinoma | 2023-05-22 | criteria provided, single submitter | clinical testing |