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

dbSNP: rs267607986

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076339	SCV000107362	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854321	SCV002180505	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-03-13	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 12 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 individuals with breast cancer and clinical features of Lynch syndrome (PMID: 16142001, 21642682, 28580595; Invitae). ClinVar contains an entry for this variant (Variation ID: 90837). 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.
Ambry Genetics	RCV002415557	SCV002724259	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-11-23	criteria provided, single submitter	clinical testing	The c.2005+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 12 of the MSH2 gene. This variant has been reported in the germline in several Lynch syndrome families to date (Sutter C et al. Int. J. Gynecol. Pathol., 2004 Jan;23:18-25; Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702; Overbeek LI et al. Br. J. Cancer, 2007 May;96:1605-12). 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. 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 likely pathogenic.
Myriad Genetics, Inc.	RCV003452873	SCV004186595	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.