ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1151G>T (p.Arg384Met) (rs730881789)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160664 SCV000211274 uncertain significance not provided 2014-06-30 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1151G>T at the cDNA level, p.Arg384Met (R384M) at the protein level, and results in the change of an Arginine to a Methionine (AGG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Arg384Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg384Met occurs at a position that is highly conserved across species and is located in the MSH2 binding site domain (Kariola 2002). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH6 Arg384Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000569549 SCV000662538 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-06 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000824400 SCV000965297 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-04-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with methionine at codon 384 of the MSH6 protein (p.Arg384Met). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and methionine. This variant is present in population databases (rs730881789, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 182619). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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