Submissions for variant NM_000251.3(MSH2):c.2006-1G>C

dbSNP: rs267607988

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076347	SCV000107373	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV000491159	SCV000580477	pathogenic	Hereditary cancer-predisposing syndrome	2020-02-27	criteria provided, single submitter	clinical testing	The c.2006-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 13 of the MSH2 gene. This mutation has been identified in multiple patients satisfying Amsterdam Criteria I (ACI) with tumors lacking MSH2 expression on IHC (Stormorken AT, J. Clin. Oncol. 2005 Jul; 23(21):4705-12; Sjursen W, J. Med. Genet. 2010 Sep; 47(9):579-85). This mutation was identified in an additional patient diagnosed at age 37 with CRC lacking MSH2 expression on IHC (Nagasaka T, Cancer Res. 2010 Apr; 70(8):3098-108), in a patient with an MSI-H tumor and/or a family history meeting AC criteria (Mangold E, Int. J. Cancer 2005 Sep; 116(5):692-702) and in a patient with colon cancer at 43 with loss of expression of MSH2 and MSH6 on IHC who also had bilateral renal cancer at ages 50 and 58 (Moussa SA et al. Int J Colorectal Dis, 2011 Apr;26:455-67). Of note, this mutation is also called IVS12-1G>C in published literature. 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.
Invitae	RCV001379378	SCV001577172	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-02-09	criteria provided, single submitter	clinical testing	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. Donor and acceptor splice site variants 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with Lynch syndrome (PMID: 15849733, 16034045, 21311894). This variant is also known as IVS12-1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 90845). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 12 of the MSH2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Myriad Genetics, Inc.	RCV003452876	SCV004186692	likely pathogenic	Lynch syndrome 1	2023-08-07	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.