ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1432C>T (p.Leu478Phe) (rs1051194508)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485109 SCV000568629 uncertain significance not provided 2016-04-20 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1432C>T at the cDNA level, p.Leu478Phe (L478F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTC>TTC). This variant has been observed in at least one individual with epithelial ovarian cancer (Pal 2012). MSH2 Leu478Phe 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. MSH2 Leu478Phe occurs at a position that is conserved across species and is located within the Clamp domain as well as the region of interaction with MSH6 and MSH3 (Lützen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Leu478Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572164 SCV000669762 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000698504 SCV000827171 uncertain significance Hereditary nonpolyposis colon cancer 2018-05-21 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 478 of the MSH2 protein (p.Leu478Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with ovarian cancer (PMID: 23047549). ClinVar contains an entry for this variant (Variation ID: 420083). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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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