Submissions for variant NM_000251.3(MSH2):c.1077-1G>T

dbSNP: rs267607944

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076020	SCV000107041	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
University of Washington Department of Laboratory Medicine, University of Washington	RCV000076020	SCV000887350	pathogenic	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH2 NM_000251.2:c.1077-1G>T has a 99.96% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.
Ambry Genetics	RCV001009855	SCV001169976	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-07	criteria provided, single submitter	clinical testing	The c.1077-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 7 of the MSH2 gene. This variant has been identified in multiple probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability, a tumor protein expression profile consistent with a MSH2 mutation and familial segregation (Arnold S et al. Hum Mutat, 2009 May;30:757-70). This variant has been identified in a proband who met Amsterdam I criteria for Lynch syndrome (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 acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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.	RCV003452801	SCV004186817	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].