ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1743G>A (p.Pro581=) (rs567838745)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165449 SCV000216179 likely benign Hereditary cancer-predisposing syndrome 2014-08-05 criteria provided, single submitter clinical testing
GeneDx RCV000420605 SCV000521670 likely benign not specified 2018-01-11 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.
Invitae RCV001084862 SCV000556008 benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000420605 SCV000601365 likely benign not specified 2017-04-21 criteria provided, single submitter clinical testing
Color RCV000165449 SCV000689838 likely benign Hereditary cancer-predisposing syndrome 2016-04-07 criteria provided, single submitter clinical testing
Counsyl RCV000662457 SCV000784935 likely benign Lynch syndrome II 2017-02-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759810 SCV000889388 likely benign not provided 2018-07-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000662457 SCV001310413 uncertain significance Lynch syndrome II 2017-05-02 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Integrated Genetics/Laboratory Corporation of America RCV000420605 SCV001362938 likely benign not specified 2019-02-12 criteria provided, single submitter clinical testing Variant summary: The variant, MLH1 c.1743G>A 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 6.1e-05 in 276996 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (6.1e-05 vs 0.00071), allowing no conclusion about variant significance. The variant, c.1743G>A has been reported in the literature in an individual affected with colorectal cancer (Crucianelli_2014). However, this report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. 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 likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

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