Submissions for variant NM_000249.4(MLH1):c.579A>G (p.Ser193=)

gnomAD frequency: 0.00004  dbSNP: rs587781038

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212520	SCV000170289	benign	not specified	2014-06-04	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	RCV000126772	SCV000214708	likely benign	Hereditary cancer-predisposing syndrome	2014-06-17	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.
Counsyl	RCV000410330	SCV000489613	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2016-10-28	criteria provided, single submitter	clinical testing
Invitae	RCV001079826	SCV000555957	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000126772	SCV000684844	likely benign	Hereditary cancer-predisposing syndrome	2015-08-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000462193	SCV001134317	likely benign	not provided	2023-02-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000126772	SCV002528754	likely benign	Hereditary cancer-predisposing syndrome	2022-03-02	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410330	SCV004018137	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-14	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.
CeGaT Center for Human Genetics Tuebingen	RCV000462193	SCV004185046	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	MLH1: BP4, BP7
PreventionGenetics, part of Exact Sciences	RCV003915264	SCV004740259	likely benign	MLH1-related disorder	2019-09-20	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).
All of Us Research Program, National Institutes of Health	RCV003997439	SCV004835302	likely benign	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000462193	SCV001549932	likely benign	not provided		no assertion criteria provided	clinical testing	The MLH1 p.Ser193= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs587781038) as "With Likely benign allele", ClinVar (classified as benign by Invitae and GeneDx; as likely benign by Ambry Genetics, Counsyl and Color), and in UMD-LSDB (3x as neutral). In UMD the variant was identified with a co-occurring likely pathogenic/pathogenic MSH2 variant (c.IVS2+1G>A (c.366+1G>A)), increasing the likelihood that the p.Ser193= variant does not have clinical significance. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Ser193= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.