ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.476G>T (p.Arg159Ile) (rs786202921)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165991 SCV000216749 uncertain significance Hereditary cancer-predisposing syndrome 2014-10-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000478310 SCV000572102 uncertain significance not provided 2016-10-21 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.476G>T at the cDNA level, p.Arg159Ile (R159I) at the protein level, and results in the change of an Arginine to an Isoleucine (AGA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Arg159Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Arg159Ile occurs at a position that is conserved across species and is located in the connector domain (Lützen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Arg159Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780455 SCV000917717 uncertain significance not specified 2018-07-31 criteria provided, single submitter clinical testing Variant summary: MSH2 c.476G>T (p.Arg159Ile) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 121412 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.476G>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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