ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.126C>G (p.Phe42Leu) (rs730881766)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212577 SCV000211201 uncertain significance not provided 2018-08-28 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.126C>G at the cDNA level, p.Phe42Leu (F42L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTC>TTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Phe42Leu was not observed in large population cohorts (Lek 2016). This variant is located in the mismatch binding domain (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 Phe42Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160605 SCV000216783 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-06 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000559519 SCV000625245 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 42 of the MSH2 protein (p.Phe42Leu). The phenylalanine residue is weakly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs730881766, ExAC 0.002%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 182574). 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: "Possibly 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.
Color RCV000160605 SCV000689967 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192614 SCV001360859 uncertain significance not specified 2019-05-24 criteria provided, single submitter clinical testing Variant summary: MSH2 c.126C>G (p.Phe42Leu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-06 in 229070 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.126C>G has been reported in the literature in at-least one female with breast cancer after the age of 50 who had a low risk based on family history and was referred for commercial BRCA1/2 testing (Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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