ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3284G>A (p.Arg1095His) (rs63750253)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164048 SCV000214655 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,Conflicting evidence
Color RCV000164048 SCV000685383 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-12 criteria provided, single submitter clinical testing
Counsyl RCV000412287 SCV000489603 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-11-02 criteria provided, single submitter clinical testing
GeneDx RCV000433110 SCV000517286 likely benign not specified 2017-10-18 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000433110 SCV000917734 uncertain significance not specified 2018-09-10 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3284G>A (p.Arg1095His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. However, multiple functional studies have found that the variant is associated with MMR activity similar to the wild-type controls (Kantelinen_2012, Kariola_2013, and Wielders_2013). The variant allele was found at a frequency of 4.5e-05 in 246222 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (4.5e-05 vs 0.00014), allowing no conclusion about variant significance. The variant, c.3284G>A, has been reported in the literature in individuals affected with Lynch Syndrome (Kariola_2013, Maxwell_2015, Wei_2016, Yurgelun_2015) with limited information (ie. lack of cosegregation and/or co-occurrence, authors classification of "neutral" or "VUS"). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS x4, likely benign x1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074835 SCV000108046 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000524168 SCV000254312 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1095 of the MSH6 protein (p.Arg1095His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs63750253, ExAC 0.006%). This variant has been reported in the literature in individuals affected with colorectal cancer (PMID: 12522549, 25980754). ClinVar contains an entry for this variant (Variation ID: 89368). Experimental studies have shown that this missense change has no effect on MSH6 mismatch repair activity, expression, or interaction with MSH2 (PMID: 12522549, 24040339, 17594722, 22581703). 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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