ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.55T>C (p.Phe19Leu) (rs141711342)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588459 SCV000211236 likely benign not provided 2021-04-27 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25503501, 22949387, 25256751)
Ambry Genetics RCV000160635 SCV000214558 likely benign Hereditary cancer-predisposing syndrome 2018-11-01 criteria provided, single submitter clinical testing 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
Invitae RCV001084278 SCV000218919 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-11-23 criteria provided, single submitter clinical testing
Counsyl RCV000409531 SCV000488058 uncertain significance Lynch syndrome I 2015-12-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588459 SCV000601485 benign not provided 2019-03-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001255213 SCV000696277 likely benign not specified 2020-08-19 criteria provided, single submitter clinical testing Variant summary: MSH2 c.55T>C (p.Phe19Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 219030 control chromosomes, predominantly at a frequency of 0.0018 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.2- fold the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.55T>C has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Thompson_2013) and breast cancer (e.g. Maxwell_2014) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrence with another pathogenic variant has been reported (MLH1 c.1624C>T, p.Gln542X; UMD database), providing supporting evidence for a benign role. At least one publication reports the varaint as non-pathogenic based on a genetic screen that assesses the MMR-abrogating effect of endogenously expressed Msh2 variants in mESCs (Houlleberghs_2016). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. These laboratories cited the variant as benign/likely benign (n=4) and uncertain significance (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000588459 SCV000806045 uncertain significance not provided 2017-08-11 criteria provided, single submitter clinical testing
Mendelics RCV000708823 SCV000837810 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000160635 SCV000910843 likely benign Hereditary cancer-predisposing syndrome 2016-04-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000409531 SCV001302261 uncertain significance Lynch syndrome I 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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