ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.790+4A>G (rs267607786)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000075854 SCV000543611 likely pathogenic Lynch syndrome 2016-06-04 criteria provided, single submitter clinical testing This variant affects a highly conserved nucleotide within the consensus splice site of intron 9. The majority of introns (73%) have a A at this position (PMID: 9536098). This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hereditary non-polyposis colorectal cancer (PMID: 9298827, 16341550) and it was reported to segregate with disease in an affected family (PMID: 16341550). ClinVar contains an entry for this variant (Variation ID: 90363). Experimental studies have shown that this variant causes abnormal splicing which creates transcripts that are lacking exon 9 or lacking exons 9 and 10 (PMID: 16341550). A different nucleotide change at the same position was also reported to produce abnormally spliced transcripts (PMID: 20717847). For these reasons, this variant has been classified as Likely Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075854 SCV000592376 pathogenic Lynch syndrome 2013-04-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV001026934 SCV001189410 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-09 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting pathogenic classification;Rarity in general population databases (dbsnp, esp, 1000 genomes);Significant disease association in appropriately sized case-control study(ies)

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