Submissions for variant NM_000179.3(MSH6):c.2743G>A (p.Ala915Thr)

dbSNP: rs1558666565

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758672	SCV000887443	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH6 NM_000179.2:c.2743G>A has a 59.6% 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.
Ambry Genetics	RCV002440585	SCV002749425	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-06	criteria provided, single submitter	clinical testing	The p.A915T variant (also known as c.2743G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 2743. The alanine at codon 915 is replaced by threonine, an amino acid with similar properties. This variant was identified in conjunction with MSH6 loss of heterozygosity in one tumor with unexplained MMRd and was classified as a variant of unknown significance by authors incorporating somatic data into a multifactorial model for variant classification (Shirts BH et al. Am. J. Hum. Genet., 2018 07;103:19-29). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV002533820	SCV003487198	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-04-07	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with MSH6-related conditions. 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 expected to disrupt MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 619580). 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 915 of the MSH6 protein (p.Ala915Thr).