Submissions for variant NM_000249.4(MLH1):c.2091C>T (p.Leu697=)

dbSNP: rs536488280

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001721372	SCV000531724	likely benign	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Invitae	RCV000526146	SCV000625125	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566789	SCV000669558	likely benign	Hereditary cancer-predisposing syndrome	2016-02-04	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.
Color Diagnostics, LLC DBA Color Health	RCV000566789	SCV000684799	likely benign	Hereditary cancer-predisposing syndrome	2015-07-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000428650	SCV000917639	likely benign	not specified	2018-02-07	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.2091C>T 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 0.0001 in 120336 control chromosomes, predominantly observed within the South Asian subpopulation at a frequency of 0.00073 in the ExAC database. This frequency is somewhat higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (0.00073 vs 0.00071), suggesting that it is a benign polymorphism predominantly observed in the South Asian subpopulation. To our knowledge, no occurrence of c.2091C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three 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	RCV000566789	SCV002528713	likely benign	Hereditary cancer-predisposing syndrome	2021-08-24	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003892132	SCV004710572	likely benign	MLH1-related disorder	2023-08-17	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	RCV004000505	SCV004843276	likely benign	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000428650	SCV000691866	likely benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357498	SCV001552984	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MLH1 p.Leu697= variant was not identified in the literature nor was it identified in the UMD-LSDB databases. The variant was also identified in ClinVar (6x as Likely Benign by GeneDx, Invitae and 4 additional clinical laboratories). The variant was identified in control databases in 21 of 245,676 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 21 of 30772 chromosomes (freq: 0.0007), while the variant was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Leu697= 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. The variant occurs outside of the splicing consensus sequence and 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.