Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000114750 | SCV000148648 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Multifactorial likelihood analysis posterior probability 0.95-0.99 |
| Ambry Genetics | RCV000129248 | SCV000184007 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-04-09 | criteria provided, single submitter | clinical testing | The p.S541R variant (also known as c.1621A>C), located in coding exon 4 of the MSH6 gene, results from an A to C substitution at nucleotide position 1621. The serine at codon 541 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been identified in several individuals who either met Amsterdam II criteria and/or had high microsatellite instability (MSI-H) in their tumor or had tumor results showing abnormal MSH6 staining on immunohistochemistry (Ambry internal data; Fokkema IF et al. Hum. Mutat., 2011 May;32:557-63; Raskin L et al. Oncotarget 2017 Nov;8(55):93450-93463). Based on internal structural analysis, p.S541R strongly perturbs the structure of the ATPase domain more than other known nearby likely pathogenic variants (Warren JJ et al. Mol. Cell, 2007 May;26:579-92). This alteration has been classified as likely pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). This amino acid position is well conserved through mammals, but not in all available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, the CoDP in silico tool predicts this alteration to impair molecular function, with a score of 0.999 (Terui H et al. J. Biomed. Sci. 2013;20:25). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV003593911 | SCV004293904 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-09-10 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 541 of the MSH6 protein (p.Ser541Arg). This variant is present in population databases (rs587779778, gnomAD 0.0009%). This missense change has been observed in individual(s) with colon cancer (PMID: 29212164). ClinVar contains an entry for this variant (Variation ID: 126891). 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 affects 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. |