ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.835C>G (p.Leu279Val) (rs375351205)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122993 SCV000166288 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 279 of the MSH2 protein (p.Leu279Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs375351205, ExAC 0.006%). This variant has been reported in individuals affected with rectal cancer (PMID: 21056691), Lynch syndrome (PMID: 18566915), and breast cancer (PMID: 26976419). This variant has also been observed in an individual in the Universal Mutation Database (PMID: 23729658). However, in that individual a pathogenic allele was also identified in MLH1, which suggests that this c.835C>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 135865). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on MSH2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000131260 SCV000186225 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000656875 SCV000292621 uncertain significance not provided 2018-03-01 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.835C>G at the cDNA level, p.Leu279Val (L279V) at the protein level, and results in the change of a Leucine to a Valine (CTC>GTC). This variant has been observed in at least two individuals being evaluated for possible Lynch syndrome, including one patient with rectal cancer at age 45 whose tumor immunohistochemistry showed retention of the MLH1 and MSH2 proteins (Nilbert 2009, Limburg 2011). Additionally, Tung et al. (2016) identified this variant in a young breast cancer patient with a family history of breast and colon cancer; however, this patient was found to also harbor a pathogenic BRCA2 variant. Lastly, this variant was identified in at least one individual undergoing mulitgene hereditary cancer panel testing, with no specific information regarding cancer history provided (Mu 2016). MSH2 Leu279Val was observed at an allele frequency of 0.01% (13/126,086) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). This variant is located in the connector domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Leu279Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000409770 SCV000488719 uncertain significance Lynch syndrome I 2016-05-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000237042 SCV000601491 uncertain significance not specified 2017-02-21 criteria provided, single submitter clinical testing
Color RCV000131260 SCV000685134 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000237042 SCV000917682 uncertain significance not specified 2018-10-05 criteria provided, single submitter clinical testing Variant summary: MSH2 c.835C>G (p.Leu279Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.1e-05 in 275108 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (5.1e-05 vs 0.00057), allowing no conclusion about variant significance. The variant, c.835C>G, has been reported in the literature in individuals affected with colorectal cancer (Limburg_Hepatol_2011, Nilbert_2009). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrence with other pathogenic variants (MLH1 c.117-1G>C; BRCA2 c.5682C>A, p.Tyr1894X) has been reported, providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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 VUS-possibly benign.

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