Submissions for variant NM_000249.4(MLH1):c.1990-1G>A

dbSNP: rs267607884

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075467	SCV000106465	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985780	SCV001134299	pathogenic	not provided	2019-06-13	criteria provided, single submitter	clinical testing	The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. Nucleotide conservation is uninformative.
Ambry Genetics	RCV001013970	SCV001174618	pathogenic	Hereditary cancer-predisposing syndrome	2019-04-01	criteria provided, single submitter	clinical testing	The c.1990-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 18 of the MLH1 gene. This mutation has been reported in a proband diagnosed with microsatellite unstable colorectal cancer whose family history met Amsterdam I criteria (Godino J et al. Hum Mutat. 2001 Dec;18(6):549). An in vitro splicing analysis demonstrated deletion of coding exon 18 (Arnold S et al. Hum Mutat. 2009 May;30(5):757-70). This alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]; Shirts BH et al. Am J Hum Genet. 2018 Jul 5;103(1):19-29). 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.
GeneDx	RCV000985780	SCV001791606	pathogenic	not provided	2019-12-24	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in an in-frame deletion of exon 18 (Caldes 2002, Arnold 2009, Thompson 2013); Not observed in large population cohorts (Lek 2016); Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (Stenson 2014, Landrum 2016); This variant is associated with the following publications: (PMID: 29887214, 15289847, 19267393, 22949379, 11920650, 11748856, 25525159)
Invitae	RCV003593880	SCV004293472	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (Invitae). ClinVar contains an entry for this variant (Variation ID: 89985). Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 11748856, 15289847; Invitae). 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 affects an acceptor splice site in intron 17 of the MLH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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).