ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.454-1G>A

dbSNP: rs193922370
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000030226 SCV000106730 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration: full inactivation of variant allele
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030226 SCV000052893 pathogenic Lynch syndrome 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Invitae RCV001067834 SCV001232915 pathogenic Hereditary nonpolyposis colorectal neoplasms 2022-07-19 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the MLH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 7584997, 8940269, 10829038, 14574010, 23544471, 27601186). It is commonly reported in individuals of Finnish ancestry (PMID: 8940269, 19931546). ClinVar contains an entry for this variant (Variation ID: 36553). Studies have shown that disruption of this splice site results in skipping of exon 6 and introduces a premature termination codon (PMID: 15235038; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018611 SCV000038894 pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 1996-12-01 no assertion criteria provided literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001725119 SCV001960033 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001725119 SCV001970851 pathogenic not provided no assertion criteria provided clinical testing
GeneReviews RCV001804749 SCV002054070 not provided Lynch syndrome 1 no assertion provided literature only

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