Submissions for variant NM_000249.4(MLH1):c.1743G>A (p.Pro581=)

gnomAD frequency: 0.00003  dbSNP: rs567838745

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165449	SCV000216179	likely benign	Hereditary cancer-predisposing syndrome	2014-08-05	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	RCV000420605	SCV000521670	likely benign	not specified	2018-01-11	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.
Invitae	RCV001084862	SCV000556008	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165449	SCV000689838	likely benign	Hereditary cancer-predisposing syndrome	2016-04-07	criteria provided, single submitter	clinical testing
Counsyl	RCV000662457	SCV000784935	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2017-02-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759810	SCV000889388	likely benign	not provided	2023-08-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000662457	SCV001310413	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-05-02	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled 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	RCV000420605	SCV001362938	likely benign	not specified	2019-02-12	criteria provided, single submitter	clinical testing	Variant summary: The variant, MLH1 c.1743G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.1e-05 in 276996 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (6.1e-05 vs 0.00071), allowing no conclusion about variant significance. The variant, c.1743G>A has been reported in the literature in an individual affected with colorectal cancer (Crucianelli_2014). However, this report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 likely benign.
Sema4, Sema4	RCV000165449	SCV002528673	benign	Hereditary cancer-predisposing syndrome	2020-11-28	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662457	SCV004018094	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-13	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
PreventionGenetics, part of Exact Sciences	RCV003975235	SCV004787732	likely benign	MLH1-related disorder	2019-04-05	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).
All of Us Research Program, National Institutes of Health	RCV003995418	SCV004843204	likely benign	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing