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

dbSNP: rs267607988

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758657	SCV000887424	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH2 NM_000251.2:c.2006-1G>T has a 86.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.20 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.
Color Diagnostics, LLC DBA Color Health	RCV001187975	SCV001354917	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-05-29	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the -1 position of intron 12 of the MSH2 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Ambry Genetics	RCV001187975	SCV002720456	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	clinical testing	The c.2006-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 13 of the MSH2 gene. Another alteration impacting the same acceptor site (c.2006-1G>C) has been detected 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor 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 a disease-causing mutation.
Myriad Genetics, Inc.	RCV003453554	SCV004186655	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.