Submissions for variant NM_000251.3(MSH2):c.1077-2A>T

dbSNP: rs267607943

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076025	SCV000107045	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV002415552	SCV002726212	pathogenic	Hereditary cancer-predisposing syndrome	2020-04-15	criteria provided, single submitter	clinical testing	The c.1077-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides upstream from coding exon 7 in the MSH2 gene. This alteration was reported in a proband whose colorectal tumor demonstrated high microsatellite instability (MSI-H) and loss of MSH2 expression on immunohistochemistry (IHC) (Ward R et al. J. Cancer Res. Clin. Oncol., 2002 Aug;128:403-11). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration at the same nucleotide position, c.1077-2A>C, has been reported as pathogenic based on being identified in a proband meeting clinical diagnostic criteria for Lynch syndrome and functional RNA studies demonstrated abnormal splicing for this variant (Ambry internal data; De Lellis L, PLoS ONE 2013 ; 8(11):e81194). 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.	RCV003452803	SCV004188110	pathogenic	Lynch syndrome 1	2023-07-31	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].
Invitae	RCV003593894	SCV004293884	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-04	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 6 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. Disruption of this splice site has been observed in individual(s) with Lynch Syndrome (PMID: 12200596, 14970868, 15849733, 24278394, 31615790). ClinVar contains an entry for this variant (Variation ID: 90530). 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. For these reasons, this variant has been classified as Pathogenic.