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

gnomAD frequency: 0.00019  dbSNP: rs28930073

Total submissions: 17

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	2024-01-31	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	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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	2023-07-06	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, part of Exact Sciences	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
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492297	SCV004240755	likely benign	Breast and/or ovarian cancer	2022-08-24	criteria provided, single submitter	clinical testing
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