Submissions for variant NM_000251.3(MSH2):c.2210+1G>A

dbSNP: rs267608002

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076423	SCV000107451	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Invitae	RCV000524382	SCV000548155	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change affects a donor 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. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12362047, 17189986, 18307539, 24710284, 30093976; Invitae). ClinVar contains an entry for this variant (Variation ID: 90921). Studies have shown that disruption of this splice site results in skipping of exon 13 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.
Ambry Genetics	RCV000490900	SCV000580436	pathogenic	Hereditary cancer-predisposing syndrome	2017-06-21	criteria provided, single submitter	clinical testing	The c.2210+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 13 of the MSH2 gene. This alteration has previously been detected in multiple individuals with early-onset colorectal cancer whose tumors demonstrated microsatellite instability and deficient MSH2 immunostaining (Yan HL et al. Cancer Sci. 2008 Apr;99(4):770-80; Ambry internal data). In addition, another alteration at this location, c.2210+1G>C, has been identified in a Lynch syndrome kindred and reported to cause an out of frame deletion of exon 13 (Kámory E et al. Pathol. Oncol. Res. 2006;12(4):228-33; Kurzawski G et al. Clin. Genet. 2006 Jan;69(1):40-7). Using the BDGP and ESEfinder splice site prediction tools, the c.2210+1G>A alteration is predicted to abolish the native donor splice site; however, direct evidence is unavailable. 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.	RCV003452895	SCV004186619	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000076423	SCV004848349	pathogenic	Lynch syndrome	2020-05-13	criteria provided, single submitter	clinical testing	The c.2210+1G>A variant in MSH2 has been reported in three individuals with MSH2-related cancers and HNPCC and segregated with disease in four affected individuals from one family (Kamory 2006, Yan 2008, Chan 2018). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 90921). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the MSH2 gene is an established disease mechanism in autosomal dominant HNPCC. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HNPCC. ACMG/AMP Criteria applied: PVS1, PM2, PP1, PS4_Supporting.