Submissions for variant NM_000249.4(MLH1):c.1820T>A (p.Leu607His)

gnomAD frequency: 0.00015  dbSNP: rs41295284

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075372	SCV000106367	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability 0.001-0.049
GeneDx	RCV001703975	SCV000149376	likely benign	not provided	2020-11-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19389263, 17510385, 18561205, 20978114, 10713887, 11839723, 21681552, 23523604, 22949387, 18566915, 23588873, 22736432, 21056691, 18033691, 15365995, 11369138, 25871441, 20978117, 26637282, 23741719, 17192056, 24933000, 15222003, 26926912, 31784484)
Ambry Genetics	RCV000115467	SCV000183756	likely benign	Hereditary cancer-predisposing syndrome	2018-09-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Invitae	RCV000524252	SCV000219095	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212544	SCV000539635	likely benign	not specified	2016-10-13	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: Variant reported in 10 papers with functional data supporting non-pathogenic. Max MAF in ExAC is 0.04%. Classified by InSiGHT as Likely Benign (3 stars in ClinVar).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000212544	SCV000592421	likely benign	not specified	2014-12-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001703975	SCV000601369	likely benign	not provided	2022-09-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115467	SCV000684773	likely benign	Hereditary cancer-predisposing syndrome	2022-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212544	SCV000696128	benign	not specified	2021-09-27	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1820T>A (p.Leu607His) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain of 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 0.00018 in 254496 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (0.00018 vs 0.00071), allowing no conclusion about variant significance. c.1820T>A has been reported in the literature in individuals affected with microsatellite stable (MSS) colorectal cancer, Lynch Syndrome or Lynch-syndrome associated cancers (e.g. Fidalgo_2000, Cravo_2002, Barnetson_2008, Valentin_2011, Castillejo_2014 ), including a family showing lack of co-segregation (Perez-Cabornero 2013). A recent study reporting tumour characteristic likelihood ratio (TCLR) for this variant, classified it as likely benign (Li_2020). The variant has been functionally characterized and shown to have no effect on splicing (Tournier 2008, Borras 2012) and MMR activity (Takahashi 2007, Houlleberghs_2020). One study (Xie 2010) indicated that the variant affects FANCJ binding which could play a role in cancer and/or chemoresistance due to a delay in MMR signaling. However, the conclusions drawn from this study remain speculative and do not allow an estimation of the risk associated with this variant. Therefore, the clinical and functional data do not allow any conclusion about variant significance. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.4137_4141delGATTA, p.Ile1380Argfs*21), providing supporting evidence for a benign role. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments and a majority consensus towards a likely benign outcome. Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000987185	SCV001136424	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000987185	SCV001305809	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.
Genetic Services Laboratory, University of Chicago	RCV000212544	SCV002066158	likely benign	not specified	2020-09-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115467	SCV002528681	likely benign	Hereditary cancer-predisposing syndrome	2020-10-26	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002498361	SCV002804553	likely benign	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2022-03-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149733	SCV003838213	likely benign	Breast and/or ovarian cancer	2023-06-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944988	SCV004761920	likely benign	MLH1-related disorder	2019-10-30	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Mayo Clinic Laboratories, Mayo Clinic	RCV000212544	SCV000691864	uncertain significance	not specified		no assertion criteria provided	clinical testing