Submissions for variant NM_000249.4(MLH1):c.1896+2T>C

dbSNP: rs267607869

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075407	SCV000106402	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Invitae	RCV001854293	SCV002245783	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-10-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as 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: 89928). Disruption of this splice site has been observed in individuals with clinical features of Lynch syndrome (PMID: 10533476, 12067992, 15849733, 21642682; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 16 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	RCV002408584	SCV002722540	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-07-01	criteria provided, single submitter	clinical testing	The c.1896+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 16 in the MLH1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration has been detected in multiple individuals with early-onset colon cancer, including a patient meeting Bethesda criteria whose tumor demonstrated high microsatellite instability and loss of MLH1 and PMS2 staining by immunohistochemistry (IHC) (Akiyama Y et al. Gastroenterology, 1997 Jan;112:33-9; Mangold E et al. Int J Cancer, 2005 Sep;116:692-702; Martin-Morales L et al. PLoS One, 2018 Sep;13:e0203885). 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV003235032	SCV003933593	likely pathogenic	not provided	2022-12-13	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 25525159, 8978340, 15849733, 30256826, 34271781)