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

dbSNP: rs267607853

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075322	SCV000106316	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberration (not quantified), 3 MSI-H tumours, co-segregates with disease & absent in 1000 genomes.
Ambry Genetics	RCV000574302	SCV000676067	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-15	criteria provided, single submitter	clinical testing	The c.1731+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 15 of the MLH1 gene. This alteration has been reported in the literature in individuals meeting Amsterdam and/or Bethesda criteria (Wijnen J et al. Am. J. Hum. Genet., 1996 Feb;58:300-7; Wijnen J et al. Am. J. Hum. Genet., 1997 Aug;61:329-35; Montera M et al. J. Med. Genet., 2000 Jul;37:E7; Hendriks Y et al. Am. J. Pathol., 2003 Feb;162:469-77; Luo DC et al. World J. Gastroenterol., 2005 Mar;11:1673-9; Sheng JQ et al. Chin J Dig Dis, 2006;7:197-205). Further, a functional analysis of this alteration via a protein truncation test by Wijnen et al. has shown that c.1731+1G>A resulted in a shorter translation product than the wild-type polypeptide. Of note, this alteration is also designated as IVS15+1 G→A in published literature. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075322	SCV000919665	pathogenic	Lynch syndrome	2018-11-20	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1731+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Wijnen_1996). The variant was absent in 245974 control chromosomes (gnomAD). The variant, c.1731+1G>A, has been reported in the literature in individuals affected with Hereditary nonpolyposis colorectal cancer (HNPCC) (Luo_2005, Montera_2000, Wijnen_1996, Sheng_2006). These data indicate that the variant is likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV002514341	SCV003525133	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	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: 15786548, 16034045, 17054581, 28449805; Invitae). This variant is also known as IVS15+1G‚ÜíA. ClinVar contains an entry for this variant (Variation ID: 89848). 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.
CeGaT Center for Human Genetics Tuebingen	RCV001579372	SCV003916423	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	MLH1: PVS1, PM2, PS1:Supporting
Myriad Genetics, Inc.	RCV003451053	SCV004190050	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].
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001250003	SCV001423904	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579372	SCV001806986	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001579372	SCV001955082	pathogenic	not provided		no assertion criteria provided	clinical testing