Submissions for variant NM_000251.3(MSH2):c.2005+1G>A

dbSNP: rs267607986

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076337	SCV000107361	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Eurofins Ntd Llc (ga)	RCV000078422	SCV000110273	pathogenic	not provided	2017-09-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001014038	SCV001174697	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-11	criteria provided, single submitter	clinical testing	The c.2005+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 12 of the MSH2 gene. This variant has been identified in a proband who met Amsterdam I/II criteria for Lynch syndrome and tumor demonstrated high microsatellite instability (MSI-H) with intact MSH2 expression by immunohistochemistry (Bécouarn Y et al. Gastroenterol. Clin. Biol. 2005;29:667-75). This alteration has also been reported in another family with Lynch syndrome (Bonadona V et al. JAMA 2011 Jun;305:2304-10). This variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated MSI-H and/or loss of MSH2/MSH6 expression by immunohistochemistry (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). 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.
Invitae	RCV001068056	SCV001233145	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-09-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in unknown protein product impact (Invitae). ClinVar contains an entry for this variant (Variation ID: 90835). Disruption of this splice site has been observed in individuals with clinical features of Lynch syndrome (PMID: 16142001, 21642682; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 12 of the MSH2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816).
Myriad Genetics, Inc.	RCV003452871	SCV004186723	likely pathogenic	Lynch syndrome 1	2023-08-04	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.