ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1182T>G (p.Phe394Leu) (rs374135434)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212598 SCV000149405 uncertain significance not provided 2018-09-19 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1182T>G at the cDNA level, p.Phe394Leu (F394L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTT>TTG). This variant was reported in an individual with familial and/or early-onset breast cancer (Jalkh 2017). MSH2 Phe394Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the Lever domain and a region of interaction with MSH6 and MSH3 (Guerrette 1998, L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Phe394Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115496 SCV000184289 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000477595 SCV000548230 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 394 of the MSH2 protein (p.Phe394Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs374135434, ExAC 0.003%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 127627). 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: "Benign"; 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.
Color RCV000115496 SCV000684913 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-03 criteria provided, single submitter clinical testing
Counsyl RCV000663103 SCV000786218 uncertain significance Lynch syndrome I 2018-03-23 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212598 SCV000884131 uncertain significance not provided 2017-11-15 criteria provided, single submitter clinical testing

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