Submissions for variant NM_000251.3(MSH2):c.2459-1G>A

dbSNP: rs1060501991

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001201394	SCV000548134	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-04-11	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. Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 15 (Invitae). ClinVar contains an entry for this variant (Variation ID: 408455). Disruption of this splice site has been observed in individuals with clinical features of Lynch Syndrome (PMID: 31615790; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 14 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 12 amino acid residue(s), but is expected to preserve the integrity of the reading-frame.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000465186	SCV000887428	likely pathogenic	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH2 NM_000251.2:c.2459-1G>A has a 98.7% probability of pathogenicity based on combining prior probability from public data with likelihood ratios of 1.56 and 1.56 to 1, generated from evidence of seeing this as a somatic mutation in two independent tumors without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.
Ambry Genetics	RCV002446811	SCV002732240	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-23	criteria provided, single submitter	clinical testing	The c.2459-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 15 of the MSH2 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 acceptor site and may result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. This variant has been identified in a proband who met Amsterdam I criteria for Lynch syndrome (Ambry internal data). In addition, this variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or loss of MSH2/MSH6 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003449127	SCV004186697	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.