Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| University of Washington Department of Laboratory Medicine, |
RCV000758604 | SCV000887358 | likely benign | Lynch syndrome | 2018-05-01 | criteria provided, single submitter | clinical testing | MSH6 NM_000179.2:c.971A>G has a 2.2% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.20 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214. |
| Invitae | RCV001301123 | SCV001490284 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-09-28 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 324 of the MSH6 protein (p.Lys324Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 619533). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function. Experimental studies have shown that this missense change does not substantially affect MSH6 function (PMID: 31965077). 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 | RCV004027159 | SCV005032945 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-12-26 | criteria provided, single submitter | clinical testing | The p.K324R variant (also known as c.971A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 971. The lysine at codon 324 is replaced by arginine, an amino acid with highly similar 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. |