Submissions for variant NM_000249.4(MLH1):c.1989+1G>C

dbSNP: rs267607879

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075456	SCV000106453	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Labcorp Genetics (formerly Invitae), Labcorp	RCV001054272	SCV001218577	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change affects a donor 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Lynch syndrome-related cancers (PMID: 10323887, 15289847, 16216036, 21520333). ClinVar contains an entry for this variant (Variation ID: 89974). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003451090	SCV004185705	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-25	criteria provided, single submitter	clinical testing	This variant is considered likely 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV004696684	SCV005199151	likely pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004943744	SCV005448456	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-08-08	criteria provided, single submitter	clinical testing	The c.1989+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 17 of the MLH1 gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). 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 likely pathogenic.