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

dbSNP: rs267607969

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076217	SCV000107235	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV000491252	SCV000580623	pathogenic	Hereditary cancer-predisposing syndrome	2020-10-16	criteria provided, single submitter	clinical testing	The c.1661+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 10 of the MSH2 gene. This mutation has been reported in an HNPCC/Lynch syndrome family that meets Amsterdam I criteria (Papp J et al. World J. Gastroenterol. 2007 May;13(19):2727-32). This mutation was reported in 1/537 French families tested for Lynch syndrome (Bonadona V et al. JAMA, 2011 Jun;305:2304-10). This variant has been identified in individuals whose Lynch syndrome associated tumors demonstrated loss of MSH2 and MSH6 staining on immunohistochemistry (Ambry internal data). This alteration was also detected once in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). Using a Bayesian analysis that incorporates tumor mutation data, this variant was classified as pathogenic (Shirts BH et al. Am J Hum Genet, 2018 07;103:19-29). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000076217	SCV000887421	pathogenic	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH2 NM_000251.2:c.1661+1G>T has a 99.4% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.
Mendelics	RCV000986676	SCV001135738	likely pathogenic	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV001070711	SCV001235979	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-01-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 90720). Disruption of this splice site has been observed in individuals with clinical features of Lynch syndrome (PMID: 12624141, 16034045, 16142001, 17569143, 21642682, 31615790, 32659967). This variant is not present in population databases (gnomAD no frequency). 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).
Fulgent Genetics, Fulgent Genetics	RCV002498366	SCV002811743	likely pathogenic	Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2	2022-04-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000986676	SCV004188180	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].