ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1128T>C (p.Asp376=) (rs267607824)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075113 SCV000106105 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research MAF >1%
Invitae RCV001080774 SCV000259719 benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Counsyl RCV000410805 SCV000488560 likely benign Lynch syndrome II 2016-04-28 criteria provided, single submitter clinical testing
GeneDx RCV000442515 SCV000513623 benign not specified 2015-07-15 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000569167 SCV000669527 likely benign Hereditary cancer-predisposing syndrome 2015-02-19 criteria provided, single submitter clinical testing
Color RCV000569167 SCV000684716 likely benign Hereditary cancer-predisposing syndrome 2016-03-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759078 SCV000888172 benign not provided 2018-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000442515 SCV000917643 benign not specified 2018-04-13 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1128T>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 observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.55 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Lynch Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1128T>C has been reported in the literature in individuals affected with Lynch Syndrome, however 9 out of the reported 18 families with c.1128T>C (Asp376) also had pathogenic mutations in MLH1, MSH2 or MSH6 (Shin_2004), strongly supporting the benign nature of this variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

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