ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.394G>C (p.Asp132His)

gnomAD frequency: 0.00019  dbSNP: rs28930073
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075697 SCV000106701 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability <0.001
GeneDx RCV000679275 SCV000149391 likely benign not provided 2019-08-20 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 19504447, 17135187, 28050887, 20176959, 17510385, 19250818, 17074586, 16685411, 15991064, 17417778, 15184898, 18383312, 18547406, 15358723, 19665066, 25871441, 23741719, 19364498, 26296696, 27181684, 23588873, 28495237, 29505604, 30840782, 30370249, 30998989)
Invitae RCV001080488 SCV000166254 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115482 SCV000186202 likely benign Hereditary cancer-predisposing syndrome 2018-11-21 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000200983 SCV000539638 uncertain significance not specified 2017-01-24 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported multiple times in HGMD, with conflicting evidence. A recent paper claims that it may be pathogenic (as predicted by a computational tool developed by the authors). The variant is classified in ClinVar as Benign by an expert panel (3 stars) in 2013 and as Likely benign by 3 additional submitters (GeneDx, Invitae, Ambry) in 2015/2016. MaxMAF is 0.06% in ExAC (high for disease prevalence)
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000200983 SCV000592357 likely benign not specified 2015-11-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679275 SCV000601399 benign not provided 2019-03-19 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115482 SCV000684826 likely benign Hereditary cancer-predisposing syndrome 2015-06-17 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679275 SCV000805970 likely benign not provided 2017-11-13 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV001149364 SCV001310312 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000200983 SCV001361918 benign not specified 2021-12-07 criteria provided, single submitter clinical testing Variant summary: MLH1 c.394G>C (p.Asp132His) results in a non-conservative amino acid change located in the N-terminal domain (IPR002099) 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 0.00021 in 251384 control chromosomes, predominantly at a frequency of 0.0032 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 4.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00071), suggesting that the variant is a benign polymorphism. In addition, the variant was reported with an even higher allele frequency in the Chinese population (in 8/150 healthy controls, i.e. with an allele frequency of 2.6%), suggesting that the variant is also frequent polymorphism in the Chinese population (Mei_2006). On the other hand, the variant c.394G>C, has been reported in the literature in individuals affected with colorectal cancer and other cancer phenotypes (e.g. Lipkin_2004, Tao_2009, Khairunnisa_2018, Dorling_2021, Perez-Cabornero_2009, Frey_2017), however these data do not allow any conclusion about variant significance. In one case, the variant was reported in a daughter with colorectal cancer but not in the mother who had endometrial cancer (Khairunnisa_2018), indicating lack of segregation of the variant with disease. In addition, a co-occurrence with another pathogenic variant has been reported (MLH1 c.1852_1854delAAG, p.Lys618del; in the UMD database), providing supporting evidence for a benign role. In a case-control study, the variant was found to confer susceptibility to colorectal cancer in an Israeli population (Lipkin_2004). In this cohort, patients with the variant usually did not have MSI, tended to be older, had fewer multiple primary tumors and had fewer first degree relatives affected with HNPCC-spectrum patients. A second case-control study in a Chinese cohort also found the variant to be associated with sporadic colorectal cancer (Tao_2009). However, another case-control study in a Chinese cohort indicated the variant not to be associated and to be a nonfunctional polymorphism in the Chinese population (Mei_2006). In functional studies, MMR activity of the variant was reported to be similar to wild-type (Plotz_2006, Martinez_2010, Takahashi_2007), however the variant was reported to reduce ATPase activity (Lipkin_2004). Nine ClinVar submitters have assessed this variant since 2014, and two classified the variant as of uncertain significance, five as likely benign, and 2 as benign. In summary, though the variant might result in attenuated protein function, and could be potentially associated with a low risk for colorectal cancer, but does not segregate with the disease and therefore is not associated with Lynch syndrome. Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory,University of Chicago RCV000200983 SCV002069947 likely benign not specified 2019-11-26 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000679275 SCV002496796 likely benign not provided 2022-01-01 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000115482 SCV002528744 likely benign Hereditary cancer-predisposing syndrome 2021-01-26 criteria provided, single submitter curation
OMIM RCV000018628 SCV000038911 risk factor Colorectal cancer, sporadic, susceptibility to 2004-07-01 no assertion criteria provided literature only
Mayo Clinic Laboratories,Mayo Clinic RCV000200983 SCV000257098 uncertain significance not specified no assertion criteria provided research

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