rs267607791
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000231790.8(MLH1):c.790+1_790+2insT variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
ENST00000231790.8 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 23
GnomAD4 genome
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
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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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1
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]. -
Hereditary nonpolyposis colon cancer Pathogenic:1
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. -
Lynch syndrome Pathogenic:1
Variant causes splicing aberration interrupting protein function: full inactivation of variant allele. Multifactorial likelihood analysis posterior probability >0.99. -
not provided Pathogenic:1
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Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
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. This variant is not present in population databases (gnomAD no frequency). 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. Invitae’s Lynch syndrome clinical variant model, which takes into account the clinical and family history, age, sex, and reported ancestry of multiple individuals with this MLH1 variant, predicts that it is pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model developed at Invitae that incorporates the clinical features of 1,370,736 individuals referred for testing at Invitae. This variant is also known as c.790+2_790+3insT and IVS9+_x0001_3insT. ClinVar contains an entry for this variant (Variation ID: 90361). 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). 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). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at