ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.457G>T (p.Gly153Cys)

dbSNP: rs1060502885
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
University of Washington Department of Laboratory Medicine, University of Washington RCV000758620 SCV000887377 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH6 NM_000179.2:c.457G>T has a 93.3% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 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.
Ambry Genetics RCV002334421 SCV002636244 likely pathogenic Hereditary cancer-predisposing syndrome 2021-01-22 criteria provided, single submitter clinical testing The p.G153C variant (also known as c.457G>T), located in coding exon 2 of the MSH6 gene, results from a G to T substitution at nucleotide position 457. The amino acid change results in glycine to cysteine at codon 153, an amino acid with highly dissimilar properties. However, this change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. Using a Bayesian analysis that incorporates tumor mutation data, this variant was classified as uncertain significance by one study (Shirts BH et al. Am J Hum Genet, 2018 07;103:19-29). Another alteration impacting the same donor site (p.G153S) has been detected in a patient with rectal cancer at age 56 that showed high microsatellite instability (MSI-H) and loss of MSH6 protein staining on IHC. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution the in silico analysis for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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