ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1284T>C (p.Asp428=)

gnomAD frequency: 0.00004  dbSNP: rs772555970
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163037 SCV000213527 likely benign Hereditary cancer-predisposing syndrome 2015-11-08 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 RCV000410355 SCV000489673 likely benign Colorectal cancer, hereditary nonpolyposis, type 2 2016-11-03 criteria provided, single submitter clinical testing
Invitae RCV001080702 SCV000555969 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-05 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000163037 SCV000689800 likely benign Hereditary cancer-predisposing syndrome 2017-08-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175374 SCV000696104 likely benign not specified 2019-06-06 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1284T>C 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 2e-05 in 251332 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1284T>C, has been reported in the literature in one individual affected with epithelial ovarian cancer (Pal_2012). The report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. One co-occurrence with another pathogenic MLH1 variant have been reported (c.1772_1775delATAG , p.Asp591fsX24), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586026 SCV000888175 likely benign not provided 2017-11-02 criteria provided, single submitter clinical testing
GeneDx RCV000586026 SCV001856941 benign not provided 2015-03-03 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000163037 SCV002528635 likely benign Hereditary cancer-predisposing syndrome 2021-05-31 criteria provided, single submitter curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003149996 SCV003838016 likely benign Breast and/or ovarian cancer 2021-11-27 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000410355 SCV004018107 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.
PreventionGenetics, part of Exact Sciences RCV003952814 SCV004771747 likely benign MLH1-related disorder 2019-11-27 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 RCV003995226 SCV004840990 likely benign Lynch syndrome 2023-11-30 criteria provided, single submitter clinical testing

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