ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.394G>C (p.Asp132His) (rs28930073)

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Total submissions: 13
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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, Partners HealthCare 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 Health, Inc 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 Clinical Services Laboratory,Illumina RCV001149364 SCV001310312 uncertain significance Lynch syndrome II 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 uncertain significance not specified 2019-09-05 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 DNA mismatch repair protein family, N-terminal 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 (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Non-Polyposis Colon Cancer (0.00021 vs 0.00071), allowing no conclusion about variant significance. c.394G>C has been reported in the literature in individuals affected with colorectal cancer (Amikam_2006, Lipkin_2004, Tao_2009, Khairunnisa_2018). 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 a case-control study, the variant was found to confer susceptibility to colorectal cancer in an Iraeli population (Lipkin_2004). In this cohort, patient with the variant usually did not have an MSI defect, 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, Mei_2006, 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. An internal sample reports the variant to co-occur with another MLH1 pathogenic variant, c.67delG, providing supporting evidence for a benign role. 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). Eight ClinVar submissions (evaluation after 2014) cite the variant as seven times likely benign/benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
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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