Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000565483 | SCV000670053 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-11-03 | criteria provided, single submitter | clinical testing | The p.A159T variant (also known as c.475G>A), located in coding exon 3 of the MSH6 gene, results from a G to A substitution at nucleotide position 475. The alanine at codon 159 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was classified as likely benign by authors using a multifactorial likelihood calculation that included molecular phenotype and somatic data (Shirts BH et al. Am. J. Hum. Genet., 2018 07;103:19-29). 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. |
| University of Washington Department of Laboratory Medicine, |
RCV000758664 | SCV000887435 | likely benign | Lynch syndrome | 2018-05-01 | criteria provided, single submitter | clinical testing | MSH6 NM_000179.2:c.475G>A has a 1.8% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214. |
| Invitae | RCV001858309 | SCV002146827 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-01-26 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 483841). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 159 of the MSH6 protein (p.Ala159Thr). |