ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1296T>G (p.Phe432Leu) (rs863224614)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197729 SCV000254272 uncertain significance Lynch syndrome 2015-08-25 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 432 of the MSH6 protein (p.Phe432Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant has not been published in the literature as a germline variant and is not present in population databases. A different missense variant involving the same codon (p.Phe432Ser) has been reported in an affected individual with endometrial cancer (PMID: 24933100). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). However, an algorithm developed specifically for the MSH6 suggests that this variant is likely to be disruptive (PMID: 23621914), but these predictions have not been confirmed by published functional studies. In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000485339 SCV000566946 likely pathogenic not provided 2016-12-28 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1296T>G at the cDNA level, p.Phe432Leu (F432L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTT>TTG). Although this variant has not been published as a germline pathogenic variant or benign polymorphism to our knowledge, it has been observed as a somatic variant in a triple negative breast tumor (Balko 2014). In addition, Dufner et al. (2000) performed in vitro functional studies on an alternate variant at the same residue, Phe432Ala, which exhibited that this variant was unable to form stable complexes, abolished DNA-binding, induced ATP hydrolysis and abolished mismatch repair activity. MSH6 Phe432Leu 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 Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. MSH6 Phe432Leu occurs at a position that is conserved across species and is located in domain I of the MutS domain and in the MSH2 binding sites (Kariola 2002, Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider MSH6 Phe432Leu to be a likely pathogenic variant.

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