Submissions for variant NM_000249.4(MLH1):c.69A>G (p.Glu23=)

gnomAD frequency: 0.00006  dbSNP: rs63750555

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000161941	SCV000211926	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162712	SCV000213173	likely benign	Hereditary cancer-predisposing syndrome	2015-01-16	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001534755	SCV000601409	likely benign	not provided	2023-05-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162712	SCV000684861	likely benign	Hereditary cancer-predisposing syndrome	2015-05-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000663024	SCV000786048	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2018-02-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000506165	SCV000917645	likely benign	not specified	2019-08-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001534755	SCV001751702	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162712	SCV002528773	likely benign	Hereditary cancer-predisposing syndrome	2020-12-31	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000663024	SCV004018103	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492660	SCV004239266	likely benign	Breast and/or ovarian cancer	2023-02-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001354478	SCV004835228	likely benign	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354478	SCV001549105	likely benign	Lynch syndrome		no assertion criteria provided	clinical testing	The MLH1 p.Glu23= variant was not identified in the literature nor was it identified in the UMD-LSDB. The variant was identified in dbSNP (ID: rs63750555) as "With Uncertain significance allele" and in ClinVar (classified as likely benign by Invitae, Ambry Genetics, Color and Counsyl; as uncertain significance by one submitter). The variant was identified in control databases in 2 of 246094 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in European population in 2 of 111564 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Glu23= 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.