ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1403G>A (p.Arg468His) (rs41295268)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564062 SCV000662362 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000148649 SCV000190364 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research
Color RCV000564062 SCV000685190 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588584 SCV000695782 uncertain significance not specified 2019-05-01 criteria provided, single submitter clinical testing MSH6 c.1403G>A (p.Arg468His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-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 3.2e-05 in 253156 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1403G>A, has been reported in the literature in individuals affected with colorectal cancer (Hampel_2008, Houlleberghs_2017). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In addition, at least one study reporting the result of genetic screen indicated this variant does not impact on MMR (mismatch repair) protein function (Houlleberghs_2017). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. An expert panel (InSIGHT) submitter classified this variant as likely benign in 2013 citing Multifactorial likelihood analysis posterior probability between 0.001-0.049. Based on the evidence outlined above, the variant was classified as as VUS-possibly benign until additional information becomes available.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074654 SCV000107856 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
Invitae RCV000524110 SCV000551260 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 468 of the MSH6 protein (p.Arg468His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs41295268, ExAC 0.01%). This variant has been reported in individuals affected with colorectal cancer (PMID: 17854147, 18033691, 18809606). ClinVar contains an entry for this variant (Variation ID: 89192). Experimental studies have shown that this missense change does not have an effect on mismatch repair activity (PMID: 28531214). 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.

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