Submissions for variant NM_000249.4(MLH1):c.790+2T>A

dbSNP: rs267607790

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075850	SCV000106865	pathogenic	Lynch syndrome	2018-10-18	reviewed by expert panel	curation	Interrupts canonical donor splice site. Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics	RCV001026933	SCV001189409	pathogenic	Hereditary cancer-predisposing syndrome	2018-04-20	criteria provided, single submitter	clinical testing	The c.790+2T>A intronic pathogenic mutation results from a T to A substitution two nucleotides after coding exon 9 in the MLH1 gene. This alteration has been detected in a HNPCC/Lynch syndrome family with early-onset colon and pancreatic cancers (Han HJ et al. Hum Mol Genet. 1995 Feb;4(2):237-42; Shin YK et al. Hum Mutat. 2004 Oct;24(4):351). Other alterations at the same splice donor site consensus sequences, c.790+1G>A and c.790+2DUPT, have been reported as pathogenic based on being identified in individuals meeting clinical criteria for HNPCC/Lynch syndrome and from functional studies utilizing patient RNA that demonstrate these alterations lead to skipping of coding exons 9 and 10 (Liu B et al. Nat. Med. 1996 Feb;2(2):169-74; Southey MC et al. J. Clin. Oncol., 2005 Sep;23:6524-32; Jenkins MA et al. Clin. Gastroenterol. Hepatol., 2006 Apr;4:489-98; Auclair J et al. Hum. Mutat. 2006 Feb;27:145-54; Arnold S et al. Hum. Mutat., 2009 May;30:757-70; Rosty C et al. BMJ Open. 2016 Feb;6(2):e010293). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Invitae	RCV001382874	SCV001581828	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-10	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 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 individuals with Lynch syndrome (PMID: 7757073, 15713769, 24710284). ClinVar contains an entry for this variant (Variation ID: 90359). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 32849802). Studies have shown that disruption of this splice site results in skipping of exon 9 and introduces a premature termination codon (PMID: 32849802). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV002291498	SCV002583562	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-01-18	criteria provided, single submitter	research	A Heterozygous 3’splice site variation in intron 9 of the MLH1 gene (chr3:g.37014546T>A; Depth: 457x) that affects the invariant GT donor splice site of exon 9 (c.790+2T>A was detected. The observed variation has previously been reported in Lynch syndrome patient observed variant c.790+2T>A The variant has not been reported in the 1000 genomes, gnomAD and our internal databases. The in silico prediction of the variant is damaging by Mutation Taster2 tool. The reference base is conserved across species.
Myriad Genetics, Inc.	RCV002291498	SCV004190044	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-17	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].