ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs117221851
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226567 SCV000284042 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 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

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