Submissions for variant NM_000249.4(MLH1):c.790+2dup

dbSNP: rs267607791

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075852	SCV000106864	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberration interrupting protein function: full inactivation of variant allele. Multifactorial likelihood analysis posterior probability >0.99.
Ambry Genetics	RCV000562561	SCV000669514	pathogenic	Hereditary cancer-predisposing syndrome	2020-02-06	criteria provided, single submitter	clinical testing	The c.790+2dupT intronic pathogenic mutation, results from a duplication of two nucleotides at nucleotide position 790 after intron 9 of the MLH1 gene. This mutation has been demonstrated to result in exon 9 & exon 9,10 skipping and was identified in multiple probands whose tumors demonstrated loss of MLH1/PMS2 expression by immunohistochemistry and/or met Amsterdam I/II criteria for HNPCC/Lynch syndrome (Liu B et al. Nat. Med. 1996 Feb;2(2):169-74; Kohonen-Corish M et al. Am. J. Hum. Genet. 1996 Oct; 59(4):818-24; Young J et al. Pathology, 2002 Dec;34:529-33; Mangold E et al. Int. J. Cancer 2005 Sep; 116(5):692-702; Southey MC et al. J. Clin. Oncol., 2005 Sep;23:6524-32; Walsh MD et al. Mod. Pathol. 2012 May; 25(5):722-30; Jenkins MA et al. Clin. Gastroenterol. Hepatol., 2006 Apr;4:489-98; Arnold S et al. Hum. Mutat., 2009 May;30:757-70; Ambry internal data). Of note, this alteration is also designated as c.790+2_+3insT, IVS9+2_+3insT, and IVS9+3insT in published literature. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000700043	SCV000828780	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-03-08	criteria provided, single submitter	clinical testing	This variant is also known as c.790+2_790+3insT and IVS9+_x0001_3insT. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exons 9-10, but is expected to preserve the integrity of the reading-frame (PMID: 8574961, 8808596, 19267393). 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: 22949379). ClinVar contains an entry for this variant (Variation ID: 90361). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 8574961, 8808596, 15849733, 16616355, 22322191). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 9 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product.
Color Diagnostics, LLC DBA Color Health	RCV000562561	SCV000905469	pathogenic	Hereditary cancer-predisposing syndrome	2018-01-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509199	SCV002819284	pathogenic	Hereditary nonpolyposis colon cancer	2022-12-06	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.790+2dupT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Four of four computational tools predict a significant impact on normal splicing, predicting the variant abolishes the canonical 5' splicing donor site. At least two publications report experimental evidence that this variant indeed affects mRNA splicing, producing transcripts skipping exon 9 or both exons 9 and 10 (e.g. Kohonen-Corish_1996, Arnold_2009). The variant was absent in 249450 control chromosomes (gnomAD). c.790+2dupT has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer, including individuals with tumors with high microsatellite instability and lacking MLH-1 expression, and cosegregation with disease in at least one family who met Amsterdam criteria (e.g. Kohonen-Corish_1996, Liu_1996, Arnold_2009). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003452769	SCV004190054	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-19	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: 11781295, 8574961].