Submissions for variant NM_000249.4(MLH1):c.974G>A (p.Arg325Gln)

gnomAD frequency: 0.00002  dbSNP: rs63750268

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075949	SCV000106968	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability 0.001-0.049
Ambry Genetics	RCV000163500	SCV000214058	likely benign	Hereditary cancer-predisposing syndrome	2018-10-30	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.
Invitae	RCV001081578	SCV000253148	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000216577	SCV000279335	likely benign	not specified	2017-10-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl	RCV000409264	SCV000488009	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2015-12-11	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000216577	SCV000595808	likely benign	not specified	2017-04-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000524326	SCV000601420	likely benign	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163500	SCV000910960	likely benign	Hereditary cancer-predisposing syndrome	2016-03-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000216577	SCV000917656	uncertain significance	not specified	2023-02-21	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.974G>A (p.Arg325Gln) results in a conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251356 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (4.4e-05 vs 0.00071), allowing no conclusion about variant significance. c.974G>A has been reported in the literature in individuals affected with Lynch Syndrome, including two families in which the variant appears to segregate with disease (two affected patients per family carrying the variant; Borras_2012, Castillejo_2014). Additionally, the variant was reported in MSI-high cancers, without strong evidence for causality (Deihimi_2017, Li_2020). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Suggesting a benign impact, functional studies including splicing assay, MMR assay, MLH1 expression and PMS2 expression, and MLH1 and PMS2 subcellular localization show the variant to have function similar to WT (Borras_2012). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as a VUS - possibly benign variant.
Sema4, Sema4	RCV000163500	SCV002528791	likely benign	Hereditary cancer-predisposing syndrome	2021-06-27	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000409264	SCV004018133	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-14	criteria provided, single submitter	clinical testing	This variant is considered likely 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: 25085752].
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492420	SCV004239268	likely benign	Breast and/or ovarian cancer	2023-03-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944990	SCV004763489	likely benign	MLH1-related disorder	2020-03-20	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).