ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1410-2_1410-1delinsCC (rs1559558071)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000709740 SCV000840009 pathogenic Lynch syndrome II 2017-07-05 criteria provided, single submitter clinical testing This c.1410-2_1410-1delinsCC variant has not been reported in public databases, nor been observed in our patient cohort. However, both c.1410-1G>C and c.1410-2A>C changes have been reported in an individual from Africa in the ExAC population database each (http://exac.broadinstitute.org/variant/3-37070274-G-C, http://exac.broadinstitute.org/variant/3-37070273-A-C) and may represent the same variant in one single individual from this population. This variant affects the invariant acceptor splice site of intron 12. While not validated for clinical use, computer-based algorithms SIFT and Polyphen-2 predict this variant to activate a cryptic splice site within exon 12 at position c.1414_1415GA, which would result in the disruption of the reading frame and a premature stop codon. This variant is thus predicted to result in a loss of function of the MLH1 protein. It is thus interpreted as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000780421 SCV000917663 likely pathogenic Lynch syndrome 2018-08-28 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1410-2_1410-1delinsCC alters two nucleotides 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: Four predict the variant abolishes a 3' acceptor site and three predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 246200 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1410-2_1410-1delinsCC in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics RCV001011400 SCV001171716 pathogenic Hereditary cancer-predisposing syndrome 2019-02-25 criteria provided, single submitter clinical testing 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
Invitae RCV001247047 SCV001420445 likely pathogenic Hereditary nonpolyposis colon cancer 2019-11-17 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 12 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). This variant has not been reported in the literature in individuals with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 585224). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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