Submissions for variant NM_000251.3(MSH2):c.2211-2A>T

dbSNP: rs267608001

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076432	SCV000107461	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Invitae	RCV001854326	SCV002305913	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-12-23	criteria provided, single submitter	clinical testing	Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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. ClinVar contains an entry for this variant (Variation ID: 90930). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15309712, 31615790, 32587781). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 13 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
GeneDx	RCV003228904	SCV003926400	pathogenic	not provided	2022-11-18	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15849733, 15309712, 31615790, 32587781)
Myriad Genetics, Inc.	RCV003452897	SCV004186629	likely pathogenic	Lynch syndrome 1	2023-08-08	criteria provided, single submitter	clinical testing	This variant is considered likely 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000076432	SCV000592545	pathogenic	Lynch syndrome		no assertion criteria provided	clinical testing	The c.2211-2A>T variant was not identified in the literature, but was identified in the HGMD and the “InSiGHT Colon Cancer Database”. The c.2211-2A>T variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. Four in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, HumanSpliceFinder) predict a difference in splicing, with an abolishment of the 3' splice acceptor site of intron 13. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.