ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1558+1G>A (rs267607832)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204627 SCV000260539 pathogenic Hereditary nonpolyposis colon cancer 2018-10-01 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 13 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in several individuals affected with Lynch syndrome (PMID: 15178966, 21286823). This splice site has also been reported as IVS13+1G in the literature. ClinVar contains an entry for this variant (Variation ID: 220185). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000223493 SCV000274273 pathogenic Hereditary cancer-predisposing syndrome 2017-10-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Integrated Genetics/Laboratory Corporation of America RCV000781542 SCV000919662 likely pathogenic Lynch syndrome 2018-09-27 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1558+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246094 control chromosomes (gnomAD). The variant, c.1558+1G>A, has been reported in the literature in at least one individual affected with Lynch Syndrome (Ishida_2018), and variants at the same nucleotide position (c.1558+1G>T, c.1558+1G>C) have been associated with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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