ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.4068G>C (p.Leu1356Phe) (rs192740549)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212694 SCV000211333 uncertain significance not provided 2017-11-29 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.4068G>C at the cDNA level, p.Leu1356Phe (L1356F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTG>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Leu1356Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. MSH6 Leu1356Phe is located in the ATPase domain and within the MSH2 binding site (Kariola 2002, Warren 2007, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Leu1356Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160704 SCV000216505 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-19 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000168081 SCV000218735 uncertain significance Hereditary nonpolyposis colon cancer 2019-10-15 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 1356 of the MSH6 protein (p.Leu1356Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs192740549, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 182651). 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 tolerated, 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.
Color RCV000160704 SCV000690439 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-08 criteria provided, single submitter clinical testing
Counsyl RCV000662520 SCV000785072 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-04-03 criteria provided, single submitter clinical testing

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