Submissions for variant NM_000249.4(MLH1):c.1460G>A (p.Arg487Gln)

gnomAD frequency: 0.00001  dbSNP: rs587778917

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218037	SCV000275866	likely benign	Hereditary cancer-predisposing syndrome	2021-09-30	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.
GeneDx	RCV000480533	SCV000571659	likely benign	not provided	2019-12-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25186627, 22290698, 30578687)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000630048	SCV000751004	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-11-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000218037	SCV000903938	likely benign	Hereditary cancer-predisposing syndrome	2016-10-16	criteria provided, single submitter	clinical testing
Division of Medical Genetics, University of Washington	RCV001257464	SCV001434264	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2020-05-05	criteria provided, single submitter	clinical testing	To our knowledge, this sequence variant has not been previously reported in the literature. This variant has an overall allele frequency of 0.00004242 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses predict that this variant may not alter protein structure/function. At this time, it is unknown whether or not this variant increases cancer risk; therefore, we interpret it as a variant of uncertain significance. BP4
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480533	SCV004220070	uncertain significance	not provided	2022-12-22	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00025 (9/35440 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 33471991 (2021), 25186627 (2015), see also LOVD (http://databases.lovd.nl/shared/genes/MLH1)),as well as in an individual with cholangiocarcinoma (PMID: 30578687 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492408	SCV004240741	uncertain significance	Breast and/or ovarian cancer	2022-07-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997113	SCV004841017	likely benign	Lynch syndrome	2023-03-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001257464	SCV004931815	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2024-03-25	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: 27363726].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004595908	SCV005090578	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004595908	SCV005203525	uncertain significance	not specified	2024-07-16	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1460G>A (p.Arg487Gln) results in a conservative amino acid change in the encoded protein sequence. Five 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 251478 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MLH1 causing Lynch Syndrome (4.4e-05 vs 0.00071), allowing no conclusion about variant significance. c.1460G>A has been reported in the literature in individuals affected with various types of cancer and/or individuals undergoing cancer testing (example: Andrikopoulou_2022, Bhai_2021, Fricke_2020, Poliani_2022, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. One publication predicts the variant to be neutral based on a consensus predictor (Ali_20112). The following publications have been ascertained in the context of this evaluation (PMID: 22290698, 36531003, 34326862, 33181636, 36356413, 25186627). ClinVar contains an entry for this variant (Variation ID: 89745). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000480533	SCV001552575	uncertain significance	not provided		no assertion criteria provided	clinical testing