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

dbSNP: rs267607790

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075851	SCV000106866	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberration interrupting protein function: full inactivation of variant allele.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812444	SCV000952757	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-02-02	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 90360). 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. This variant is also known as IVS9+2T>C. 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).
Ambry Genetics	RCV002415547	SCV002677251	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-02	criteria provided, single submitter	clinical testing	The c.790+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 9 in the MLH1 gene. This alteration was identified in individuals meeting Amsterdam criteria for Lynch syndrome or with personal and family histories consistent with Lynch syndrome (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20; Casey G et al. JAMA, 2005 Feb;293:799-809; Choi YH et al. Hered Cancer Clin Pract, 2009 Aug;7:14; Ferguson SE et al. Cancer, 2014 Dec;120:3932-9). Other alterations impacting the same donor site (c.790+1G>A and c.790+2dupT) have been identified in individuals meeting Amsterdam criteria and associated with abnormal splicing (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; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). 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.
Myriad Genetics, Inc.	RCV003452768	SCV004186363	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. Functional studies indicate this variant impacts protein function [PMID: 8574961, 11781295].
Baylor Genetics	RCV003452768	SCV004193037	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353965	SCV000592373	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The c.790+2T>C variant has been reported in the literature in at least one report in an individual with HNPCC. The variant was shown to cause loss of MLH1 expression and deletion of exons 9-10 (exon skipping in cDNA), suggesting it is pathogenic (Casey_2005_15713769). In addition, our laboratory has identified this variant in one family with Lynch syndrome and evidence of MSI high tumours that were MLH1 defecient. Furthermore, the variant occurs in the splice consensus sequence region, and this type of variant is an established mechanism for loss of normal splicing of the MLH1 gene and of the type which is expected to cause the disorder. In summary, based on the above information, this variant is classified as pathogenic.