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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