Submissions for variant NM_000249.4(MLH1):c.1731+1G>C

dbSNP: rs267607853

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075323	SCV000106317	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Invitae	RCV000693129	SCV000820985	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 15 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 clinical features of Lynch syndrome (PMID: 11208710, 16034045, 17054581, 20587412; Invitae). This variant is also known as IVS15+1 G>C. ClinVar contains an entry for this variant (Variation ID: 89849). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000075323	SCV000887324	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MLH1 NM_000249.3:c.1731+1G>C has a 98.1% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.
Ambry Genetics	RCV002408576	SCV002715675	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-11	criteria provided, single submitter	clinical testing	The c.1731+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 15 of the MLH1 gene. This variant (referred to as IVS15+1G>C) has been reported in the germline of an individual with MLH1-deficient colorectal cancer diagnosed at age 31 whose family history met Amsterdam II criteria (Stormorken AT et al. J. Clin. Oncol., 2005 Jul;23:4705-12). This variant has been detected in the presence of copy-neutral loss of heterozygosity in a MSI-high, MLH1/PMS2-deficient colon cancer (Ambry internal data). 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. 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 pathogenic.
Myriad Genetics, Inc.	RCV003451054	SCV004190066	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-21	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].