ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.55T>C (p.Phe19Leu) (rs141711342)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160635 SCV000214558 likely benign Hereditary cancer-predisposing syndrome 2017-10-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,No disease association in small case-control study,Other data supporting benign classification
Color RCV000160635 SCV000910843 likely benign Hereditary cancer-predisposing syndrome 2016-04-11 criteria provided, single submitter clinical testing
Counsyl RCV000409531 SCV000488058 uncertain significance Lynch syndrome I 2015-12-18 criteria provided, single submitter clinical testing
GeneDx RCV000588459 SCV000211236 uncertain significance not provided 2017-12-22 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.55T>C at the cDNA level, p.Phe19Leu (F19L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTC>CTC). This variant was observed in at least one individual with a colon tumor that was microsatellite stable with MSH2 present on immunohistochemistry, and in at least one woman with early-onset breast cancer and no identifiable BRCA1/2 pathogenic variant (Thompson 2013, Maxwell 2014). MSH2 Phe19Leu was observed at an allele frequency of 0.20% (41/20896) in individuals of African ancestry in large population cohorts (Lek 2016). MSH2 Phe19Leu is located in the mismatch binding domain (Lutzen 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 Phe19Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588459 SCV000696277 likely benign not provided 2017-02-09 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.55T>C (p.Phe19Leu) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 18/51288 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.003637 (17/4674). This frequency is about 6 times the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. This variant has been reported in patients with early-onset breast cancer and HNPCC without strong evidence for causality. UMD reports this variant in a patient with co-occurrence of MLH1 c. 1624C>T (p.Gln542X) and IHC results being MSI / MLH1-MSH2+, suggesting this variant is likely neutral. In addition, a functional study using a genetic screen that assesses the MMR-abrogating effect of endogenously expressed Msh2 VUS in mESCs did not detect variant with any MMR defective effect and classified variant as non-pathogenic (Houlleberghs_PNAS_2016). Multiple clinical diagnostic laboratories classified this variant as VUS, another clinical lab and UMD classified this variant as likely benign, all without evidence for independent evaluation. Taken together, considering this variant is classified as likely benign.
Invitae RCV000168248 SCV000218919 likely benign Hereditary nonpolyposis colon cancer 2018-01-08 criteria provided, single submitter clinical testing
Mendelics RCV000708823 SCV000837810 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000588459 SCV000806045 uncertain significance not provided 2017-08-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212576 SCV000601485 uncertain significance not specified 2016-10-12 criteria provided, single submitter clinical testing

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