ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3809T>A (p.Met1270Lys)

gnomAD frequency: 0.00001  dbSNP: rs777617756
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570586 SCV000662521 uncertain significance Hereditary cancer-predisposing syndrome 2022-08-03 criteria provided, single submitter clinical testing The p.M1270K variant (also known as c.3809T>A), located in coding exon 9 of the MSH6 gene, results from a T to A substitution at nucleotide position 3809. The methionine at codon 1270 is replaced by lysine, an amino acid with similar properties. 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000630109 SCV000751065 benign Hereditary nonpolyposis colorectal neoplasms 2023-11-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174877 SCV001338277 uncertain significance not specified 2020-02-07 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3809T>A (p.Met1270Lys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251042 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3809T>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx RCV003126822 SCV003803340 uncertain significance not provided 2023-02-10 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22949387, 17531815, 21120944, 31257224)

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