Submissions for variant NM_000249.4(MLH1):c.207+1G>T

dbSNP: rs267607718

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075506	SCV000106502	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854295	SCV002237447	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-07-27	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 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 (ExAC no frequency). Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 15849733, 16142001, 27978560; Invitae). ClinVar contains an entry for this variant (Variation ID: 90021). 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.
Ambry Genetics	RCV002415534	SCV002729766	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-18	criteria provided, single submitter	clinical testing	The c.207+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 2 of the MLH1 gene. This alteration was identified in a proband from a family meeting Amsterdam II criteria. This proband was diagnosed with early-onset colorectal cancer, and the tumor exhibited microsatellite instability and was absent for MLH1 on immunohistochemistry (Lastella P et al. Fam. Cancer. 2011 Jun;10(2):285-95). This alteration has also been reported in an individual with Lynch syndrome (Mangold E et al. Int. J. Cancer 2005 Sep;16(5):692-702). In addition, this mutation has been identified in probands whose Lynch syndrome-associated tumor demonstrated loss of MLH1/PMS2 expression by IHC (Ambry internal data). 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). 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.
Myriad Genetics, Inc.	RCV003455992	SCV004186453	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-14	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].