ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.824G>C (p.Ser275Thr)

gnomAD frequency: 0.00001  dbSNP: rs774586054
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002027023 SCV002316462 benign Hereditary nonpolyposis colorectal neoplasms 2022-10-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV002425429 SCV002681868 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-09 criteria provided, single submitter clinical testing The p.S275T variant (also known as c.824G>C), located in coding exon 4 of the MSH6 gene, results from a G to C substitution at nucleotide position 824. The serine at codon 275 is replaced by threonine, an amino acid with similar properties. This variant has been reported in studies of whole-exome sequencing in patients with features of PTEN hamartoma tumor syndrome and negative PTEN testing, but it was not identified in the cohort of patients with features of PTEN hamartoma tumor syndrome and was instead identified in the cohort made up of patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352; Lee YR et al. N Engl J Med, 2020 05;382:2103-2116). 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.
All of Us Research Program, National Institutes of Health RCV004011154 SCV004840814 uncertain significance Lynch syndrome 2023-12-18 criteria provided, single submitter clinical testing This missense variant replaces serine with threonine at codon 275 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in at least one colorectal cancer individual and non-affected individuals (PMID: 29684080, 32459922). This variant has been identified in 2/251074 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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