ClinVar Miner

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

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Total submissions: 4
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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 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.
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001250003 SCV001423904 pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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