ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1039-1G>A (rs267607819)

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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) RCV000075088 SCV000106082 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration (not quantified), 2 MSI-H tumours, segregation with disease & absent in 1000 genomes
GeneDx RCV000153506 SCV000211092 pathogenic not provided 2016-05-17 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.1039-1G>A or IVS11-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 11 of the MLH1 gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. MLH1 c.1039-1G>A is classified as pathogenic by the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT, Thompson 2014) and has been reported in a large Finnish kindred meeting Amsterdam criteria, with colon and endometrial tumors from several individuals demonstrating microsatellite instability and loss of MLH1 expression (Holmberg 1998, Schweizer 2001) as well as another Finnish individual with ovarian cancer whose tumor was microsatellite instable and lacked MLH1 expression (Niskakoski 2013). Based on currently available information, we consider this variant to be pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000153506 SCV000700694 pathogenic not provided 2014-02-24 criteria provided, single submitter clinical testing
Invitae RCV001201713 SCV001372799 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-06-30 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 11 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Lynch Syndrome (PMID: 9322509, 26681312, 28944238). ClinVar contains an entry for this variant (Variation ID: 89619). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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