ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.790+2dup (rs267607791)

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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) RCV000075852 SCV000106864 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration interrupting protein function: full inactivation of variant allele. Multifactorial likelihood analysis posterior probability >0.99.
Ambry Genetics RCV000562561 SCV000669514 pathogenic Hereditary cancer-predisposing syndrome 2018-09-28 criteria provided, single submitter clinical testing Functionally-validated splicing mutation;Other strong data supporting pathogenic classification;Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000700043 SCV000828780 pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-07-17 criteria provided, single submitter clinical testing This sequence change falls in intron 9 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals and families suspected of Lynch syndrome and was reported segregate with disease at least in two families (PMID: 8574961, 15849733, 22322191, 8808596, 16616355). This variant is also known as c.790+2_790+3insT and IVS9+_x0001_3insT in the literature. ClinVar contains an entry for this variant (Variation ID: 90361). Based on a multifactorial likelihood algorithm using genetic, clinical, functional and in silico data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing and results in skipping of exon 9 and 10 (PMID: 8574961, 8808596), at a level far greater than the low-level alternate splicing reported in normal cells (PMID: 7728749, 9490293). This alternate splicing results in the loss of amino acids 227-295 in the MLH1 protein, which has been shown functionally to render MLH1 defective in mismatch repair activity (PMID: 11781295). For these reasons, this variant has been classified as Pathogenic.
Color RCV000562561 SCV000905469 pathogenic Hereditary cancer-predisposing syndrome 2018-01-09 criteria provided, single submitter clinical testing

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