Submissions for variant NM_000249.4(MLH1):c.453+1G>T

dbSNP: rs267607750

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075712	SCV000106716	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
GeneDx	RCV000160522	SCV000211088	likely pathogenic	not provided	2018-09-18	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.453+1G>T or IVS5+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 5 of the MLH1 gene. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in at least one individual who was reported to have colon, jejunum and renal cancer all under the age of 50 (Zhang 2015). We consider this variant to be likely pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000075712	SCV000592359	pathogenic	Lynch syndrome	2014-10-10	criteria provided, single submitter	clinical testing
Counsyl	RCV000576794	SCV000677752	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2016-12-13	criteria provided, single submitter	clinical testing
Invitae	RCV000704046	SCV000832979	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-03-14	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 90223). Disruption of this splice site has been observed in individual(s) with Lynch syndrome-related cancer (PMID: 18931482, 23747338, 25892863, 26681312). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 5 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).
Ambry Genetics	RCV001022649	SCV001184409	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-09-11	criteria provided, single submitter	clinical testing	The c.453+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 5 of the MLH1 gene. This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated low microsatellite instability and loss of MLH1/PMS2 expression by immunohistochemistry (Sheng JQ et al. Cytogenet. Genome Res. 2008 Oct;122:22-7; Zhang JX et al. World J. Gastroenterol., 2015 Apr;21:4136-49; de Voer RM et al. Gastroenterology, 2013 Sep;145:544-7). This alteration was also identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet Med, 2016 08;18:823-32). This variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or loss of PMS2 or MLH1/PMS2 expression by immunohistochemistry (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; however, direct evidence is insufficient at this time (Ambry internal 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 likely pathogenic.
Myriad Genetics, Inc.	RCV000576794	SCV004018164	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-15	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].
Baylor Genetics	RCV000576794	SCV004193033	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-10-20	criteria provided, single submitter	clinical testing