ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.233G>A (p.Arg78Lys) (rs864622425)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203940 SCV000260605 uncertain significance Hereditary nonpolyposis colon cancer 2019-09-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 78 of the MSH6 protein (p.Arg78Lys). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and lysine. This variant is not present in population databases and has not been reported in the literature. The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. In addition, algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this is a novel missense change that is not predicted to affect protein function or cause disease. However the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000561944 SCV000676110 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-19 criteria provided, single submitter clinical testing Insufficient evidence
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030487 SCV001193641 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV001139580 SCV001299753 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Integrated Genetics/Laboratory Corporation of America RCV001174583 SCV001337762 uncertain significance not specified 2020-01-10 criteria provided, single submitter clinical testing Variant summary: MSH6 c.233G>A (p.Arg78Lys) results in a conservative amino acid change located in the PWWP domain (IPR000313) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 60512 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.233G>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. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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