Submissions for variant NM_000249.4(MLH1):c.589-1G>T

dbSNP: rs587779027

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075779	SCV000106789	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Invitae	RCV001070764	SCV001236032	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-01-20	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. Disruption of this splice site has been observed in individuals affected with Lynch syndrome (LS) or clinical features of LS (PMID: 12658575, 12067992, 15178966). This variant is also known as IVS7-1G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 90290). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 7 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).
Sema4, Sema4	RCV002258789	SCV002528757	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-04-19	criteria provided, single submitter	curation
Ambry Genetics	RCV002258789	SCV002653611	pathogenic	Hereditary cancer-predisposing syndrome	2020-10-15	criteria provided, single submitter	clinical testing	The c.589-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 8 of the MLH1 gene. This mutation, designated as IVS7-1G>T, has been reported in a family meeting Amsterdam criteria (Wagner A et al. Am J Hum Genet, 2003 May;72:1088-100). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. 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.
Fulgent Genetics, Fulgent Genetics	RCV002483124	SCV002792208	likely pathogenic	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2022-02-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003452754	SCV004190030	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. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].