ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1133G>A (p.Arg378Lys) (rs587779205)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479933 SCV000567007 uncertain significance not provided 2016-12-27 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1133G>A at the cDNA level, p.Arg378Lys (R378K) at the protein level, and results in the change of an Arginine to a Lysine (AGA>AAA). This variant was observed in one individual with early-onset endometrial cancer, who also carried a familial MSH6 nonsense variant (Jori 2015). MSH6 Arg378Lys 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 Lysine share similar properties, this is considered a conservative amino acid substitution. MSH6 Arg378Lys occurs at a position that is conserved across species and is located within the MSH2 binding site and MutS domain I (Kariola 2002, Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Arg378Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000569385 SCV000662406 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-04 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000569385 SCV000690174 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-04 criteria provided, single submitter clinical testing
Invitae RCV000629837 SCV000750793 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 378 of the MSH6 protein (p.Arg378Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Lynch syndrome in the Leiden Open-source Variation Database (PMID: 21520333) and in the Universal Mutation Database (PMID: 10612827). However, in these individuals a pathogenic allele was also identified in MSH6, which suggests that this c.1133G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 89173). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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