Submissions for variant NM_000251.3(MSH2):c.2211-1G>A

dbSNP: rs267607979

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001378014	SCV001575485	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-10-05	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. 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: 635371). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 13 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).
Ambry Genetics	RCV002424783	SCV002728749	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-10-18	criteria provided, single submitter	clinical testing	The c.2211-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 14 of the MSH2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.	RCV003453621	SCV004186752	likely pathogenic	Lynch syndrome 1	2023-08-08	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.
Color Diagnostics, LLC DBA Color Health	RCV002424783	SCV004356730	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-17	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the -1 position of intron 13 of the MSH2 gene. Splice site prediction tools predict that this variant disrupts the acceptor site at exon 14 and may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, exon 14 is out-of-frame and this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with MSH2-related disorders 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.
All of Us Research Program, National Institutes of Health	RCV004001545	SCV004815137	likely pathogenic	Lynch syndrome	2023-03-02	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice site and is predicted to result in abnormal splicing. Aberrant splicing and/or loss of function is an established mechanism of disease. This prediction has not been confirmed by functional studies. This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV000786796	SCV000925686	not provided	not provided		no assertion provided	in vitro