Submissions for variant NM_000249.4(MLH1):c.1733A>G (p.Glu578Gly)

gnomAD frequency: 0.00006  dbSNP: rs63751612

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075342	SCV000106336	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability <0.001
Ambry Genetics	RCV000163055	SCV000213549	likely benign	Hereditary cancer-predisposing syndrome	2018-07-30	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524247	SCV000253135	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV001535418	SCV000279083	likely benign	not provided	2020-09-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21404117, 15184898, 8521398, 18373977, 17192056, 18566915, 18383312, 19697156, 22290698, 17594722, 10037723, 17510385, 20020535, 20978114, 17312306, 15494688, 12658575, 11304573, 11474654, 10564582, 10598809, 9697702, 22753075, 15864295, 23403630, 12810663)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000075342	SCV000296890	uncertain significance	Lynch syndrome	2015-10-12	criteria provided, single submitter	clinical testing
Counsyl	RCV000018621	SCV000488113	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2015-12-29	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000222490	SCV000539650	uncertain significance	not specified	2016-08-12	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: Several publications in HGMD describe as nonpathogenic based on functional characterizations
Color Diagnostics, LLC DBA Color Health	RCV000163055	SCV000902845	likely benign	Hereditary cancer-predisposing syndrome	2015-03-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000018621	SCV001310412	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	RCV000222490	SCV001338350	benign	not specified	2020-02-10	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1733A>G (p.Glu578Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein, mlh1, C-terminal domain (IPR032189) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251238 control chromosomes, predominantly at a frequency of 0.00024 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (0.00012 vs 0.00071), allowing no conclusion about variant significance. c.1733A>G has been reported in the literature in individuals affected with features similar to but not fulfilling the classic diagnostic criteria associated with Lynch syndrome (example, Tanngergard_1995). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least one co-occurrence with another pathogenic MLH1 variant has been reported in a family with Lynch syndrome (Wagner_2003, MLH1 deletion of exons 1-13), providing additional evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function with contradictory findings across dominant mutator effect (DME) assays in yeast model systems, in-vitro MMR activity, and protein-protein interaction with hPMS2 and hMRE11 (example, Shimodaira_1998, Guerrette_1999, Kondo_2003, Ou_2007, Takahashi_2007, Ali_2012). Subsequent reports evaluating expression, stability and MMR activity in conjunction with clinical data have demonstrated no damaging effect of this variant resulting in a categorical classification as a neutral MLH1 variant (example, Vo_2005, Andersen_2012, Hinrichsen_2013). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments as benign/likely benign (n=4), and VUS (n=3). Additionally an expert panel (InSight) has classified this variant as benign before 2014. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000222490	SCV002046136	likely benign	not specified	2021-01-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163055	SCV002528671	likely benign	Hereditary cancer-predisposing syndrome	2021-05-19	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000222490	SCV002550844	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000018621	SCV004018627	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-11-16	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic.
OMIM	RCV000018621	SCV000038904	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2010-08-01	no assertion criteria provided	literature only