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

dbSNP: rs267607879

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075457	SCV000106454	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
PreventionGenetics, part of Exact Sciences	RCV000679272	SCV000805963	pathogenic	not provided	2018-01-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075457	SCV000917659	likely pathogenic	Lynch syndrome	2018-08-13	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1989+1G>T 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: Five predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 245820 control chromosomes (gnomAD). c.1989+1G>T has been reported in the literature in an individual affected with Lynch Syndrome (Lamberti_1999). This data does not allow a conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000794468	SCV000933878	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-04-01	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 and likely results in an absent or disrupted protein product. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants 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 has been observed in a family affected with Lynch syndrome (PMID: 10323887, 16216036). ClinVar contains an entry for this variant (Variation ID: 89975). This variant is not present in population databases (ExAC no frequency).
Color Diagnostics, LLC DBA Color Health	RCV001180388	SCV001345311	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-12-13	criteria provided, single submitter	clinical testing	This variant causes a G>T nucleotide substitution at the +1 position of intron 17 of the MLH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. This variant has been reported in individuals from Lynch syndrome families (PMID 10323887, 16216036) and with suspected Lynch syndrome (PMID 15849733). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
Ambry Genetics	RCV001180388	SCV002717551	pathogenic	Hereditary cancer-predisposing syndrome	2018-05-07	criteria provided, single submitter	clinical testing	The c.1989+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 17 of the MLH1 gene. This variant has been reported in a German Lynch syndrome family meeting Amsterdam I criteria, containing three MSI-High tumors and segregating with disease in 3/3 affected individuals (Lamberti C et al. Gut, 1999 Jun;44:839-43; Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702; Mangold E et al. J. Pathol., 2005 Dec;207:385-95). 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/]). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000679272	SCV004026185	pathogenic	not provided	2022-11-02	criteria provided, single submitter	clinical testing	PVS1, PP3, PM2_SUP