Submissions for variant NM_000251.3(MSH2):c.1661+1G>A

dbSNP: rs267607969

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076216	SCV000107234	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Invitae	RCV000627711	SCV000284118	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-05-12	criteria provided, single submitter	clinical testing	This variant is also known as IVS10+1G>A. This sequence change affects a donor splice site in intron 10 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 12624141, 16034045, 16142001, 21642682). ClinVar contains an entry for this variant (Variation ID: 90719). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000986675	SCV001135737	likely pathogenic	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399455	SCV002707203	pathogenic	Hereditary cancer-predisposing syndrome	2020-04-03	criteria provided, single submitter	clinical testing	The c.1661+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 10 of the MSH2 gene. This variant has been reported in multiple Lynch syndrome/HNPCC families and is also referred to as IVS10+1G>A (Bécouarn Y et al. Gastroenterol. Clin. Biol.;29:667-75; Parc Y et al. J. Med. Genet., 2003 Mar;40:208-13; Stormorken AT et al. J. Clin. Oncol., 2005 Jul;23:4705-12; Bonadona V et al. JAMA, 2011 Jun;305:2304-10). Two pathogenic variants, c.1661+1G>T and c.1661+2T>C, which also affect this canonical splice site, have also been reported (Papp J et al. World J. Gastroenterol. 2007 May;13(19):2727-32; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465505	SCV002760644	likely pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
GeneDx	RCV002465505	SCV003853105	pathogenic	not provided	2022-09-29	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in multiple individuals with a personal and/or family history consistent with pathogenic variants in this gene (Parc et al., 2003; Kamiza et al., 2015; de Angelis de Carvalho et al., 2020), at least one with concordant tumor studies (Stormorken et al., 2005); This variant is associated with the following publications: (PMID: 25525159, 33825202, 16142001, 31830689, 26053027, 31773066, 20587412, 32659967, 12624141, 16034045)
Myriad Genetics, Inc.	RCV000986675	SCV004187936	pathogenic	Lynch syndrome 1	2023-08-03	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. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 18561205].