ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3450A>C (p.Leu1150Phe) (rs762134820)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000213324 SCV000279277 uncertain significance not provided 2017-01-30 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3450A>C at the cDNA level, p.Leu1150Phe (L1150F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTA>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Leu1150Phe 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 Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. MSH6 Leu1150Phe occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located within the ATP binding motif (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 Leu1150Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000456211 SCV000551248 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 1150 of the MSH6 protein (p.Leu1150Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs762134820, 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: 234462). 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.
Ambry Genetics RCV000491638 SCV000580209 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-24 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000491638 SCV000911940 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-03 criteria provided, single submitter clinical testing

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