ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1731+1G>A (rs267607853)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075322 SCV000106316 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration (not quantified), 3 MSI-H tumours, co-segregates with disease & absent in 1000 genomes.
Ambry Genetics RCV000574302 SCV000676067 pathogenic Hereditary cancer-predisposing syndrome 2017-08-01 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,Functionally-validated splicing mutation
Integrated Genetics/Laboratory Corporation of America RCV000075322 SCV000919665 pathogenic Lynch syndrome 2018-11-20 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1731+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: Four predict the variant abolishes a 5 splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Wijnen_1996). The variant was absent in 245974 control chromosomes (gnomAD). The variant, c.1731+1G>A, has been reported in the literature in individuals affected with Hereditary nonpolyposis colorectal cancer (HNPCC) (Luo_2005, Montera_2000, Wijnen_1996, Sheng_2006). These data indicate that the variant is likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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