Submissions for variant NM_000249.4(MLH1):c.843A>C (p.Ala281=)

gnomAD frequency: 0.00012  dbSNP: rs146796765

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212527	SCV000211134	benign	not specified	2014-07-11	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.
Ambry Genetics	RCV000160556	SCV000212895	likely benign	Hereditary cancer-predisposing syndrome	2014-07-25	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	RCV001079243	SCV000253147	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160556	SCV000537426	likely benign	Hereditary cancer-predisposing syndrome	2015-05-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000212527	SCV000592383	likely benign	not specified	2013-08-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586205	SCV000696184	likely benign	not provided	2017-08-09	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.843A>C (p.Ala281Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 12/121410 control chromosomes at a frequency of 0.0000988, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212527	SCV000889405	benign	not specified	2022-01-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001145068	SCV001305706	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). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798552	SCV002042085	likely benign	Breast and/or ovarian cancer	2023-01-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160556	SCV002528782	likely benign	Hereditary cancer-predisposing syndrome	2021-04-02	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000586205	SCV003916420	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	MLH1: BP4, BP7
PreventionGenetics, part of Exact Sciences	RCV003952800	SCV004772878	likely benign	MLH1-related disorder	2019-07-18	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	RCV003998468	SCV004840914	likely benign	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000212527	SCV000691851	likely benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000160556	SCV000788027	likely benign	Hereditary cancer-predisposing syndrome	2017-10-16	no assertion criteria provided	clinical testing