Submissions for variant NM_000249.4(MLH1):c.1990-6G>A

gnomAD frequency: 0.00001  dbSNP: rs117221851

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000226567	SCV000284042	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-17	criteria provided, single submitter	clinical testing
GeneDx	RCV001533528	SCV000513631	likely benign	not provided	2019-08-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31386297, 29338689)
Color Diagnostics, LLC DBA Color Health	RCV000580651	SCV000684788	likely benign	Hereditary cancer-predisposing syndrome	2015-04-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000663093	SCV000786196	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2018-03-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000430988	SCV000919644	benign	not specified	2021-03-19	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1990-6G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 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 6.4e-05 in 250998 control chromosomes, predominantly at a frequency of 0.00076 within the East Asian subpopulation in the gnomAD database. However, the variant was reported in some East Asian subpopulations with an even higher allele frequency, e.g. in the Japanese, with an allele frequency of 0.0112 (in the jMorp database). This frequency is about 16-fold higher than the maximum expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.1990-6G>A, has been reported in the literature in 4 Japanese individuals affected with colorectal cancer (Kiyozumi_2019), however two of the associated tumors were analyzed, and microsatellites were found to be stable and all MMR proteins were present. This report therefore does not support the association of the variant with Lynch Syndrome. Co-occurrences with other (likely) pathogenic variants have been reported (e.g. APC c.3184_3187delCAAA (p.Gln1062ValfsX63), in an internal LCA sample; MEN1 c.974C>T (p.Pro325Leu) in Shinriki_2020), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two laboratories classified the variant as benign, three as likely benign, while one laboratory classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000663093	SCV001136432	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2019-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000430988	SCV001470333	benign	not specified	2020-08-12	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000430988	SCV002071930	likely benign	not specified	2021-10-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000580651	SCV002528702	likely benign	Hereditary cancer-predisposing syndrome	2021-10-27	criteria provided, single submitter	curation
Ambry Genetics	RCV000580651	SCV002718565	likely benign	Hereditary cancer-predisposing syndrome	2015-10-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Myriad Genetics, Inc.	RCV000663093	SCV004020243	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-10	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
PreventionGenetics, part of Exact Sciences	RCV003929936	SCV004744026	likely benign	MLH1-related condition	2020-04-16	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).