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

dbSNP: rs267607853

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075324	SCV000106318	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Counsyl	RCV000576509	SCV000677751	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2017-04-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075324	SCV000696120	likely pathogenic	Lynch syndrome	2017-02-07	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.1731+1G>T variant involves the alteration of a conserved intronic nucleotide. Mutation Taster predicts a damaging outcome for this variant. 4/5 splice prediction tools predict a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 121174 control chromosomes. In addition, one reputable database classified this variant as likely pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and clinical diagnostic laboratories. Taken together, this variant is classified as likely pathogenic.
Invitae	RCV000685725	SCV000813217	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-09	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: 8571956, 15365995, 16034045, 17054581, 28449805, 34178123; Invitae). ClinVar contains an entry for this variant (Variation ID: 89850). 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.
GeneDx	RCV001567027	SCV001790640	likely pathogenic	not provided	2019-08-01	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30068706, 24362816, 21520333, 28449805, 15713769)
Ambry Genetics	RCV002408577	SCV002715676	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-26	criteria provided, single submitter	clinical testing	The c.1731+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 15 of the MLH1 gene. This alteration was identified once in a Hispanic Lynch syndrome cohort (Sunga AY et al. Cancer Genet. 2017 04;212-213:1-7). This alteration has also been identified in probands who met Amsterdam I criteria for Lynch syndrome and/or had a colorectal tumor that demonstrated high microsatellite instability with loss of both MLH1/PMS2 expression by immunohistochemistry (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data, 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.	RCV000576509	SCV004018206	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-16	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: 25085752].