Submissions for variant NM_000548.5(TSC2):c.5068+2T>C

dbSNP: rs397515152

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521796	SCV000617955	pathogenic	not provided	2015-12-23	criteria provided, single submitter	clinical testing	The c.5068+2 T>C splice site variant in the TSC2 gene destroys the canonical splice donor site in intron 2. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Many other splice variants have been reported in the Human Gene Mutation Database in association with tuberous sclerosis (Stenson et al., 2014).
Invitae	RCV000704780	SCV000833744	pathogenic	Tuberous sclerosis 2	2022-03-23	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: 449636). Disruption of this splice site has been observed in individual(s) with tuberous sclerosis complex (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 39 of the TSC2 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 TSC2 are known to be pathogenic (PMID: 10205261, 17304050).
Mendelics	RCV000704780	SCV001139766	pathogenic	Tuberous sclerosis 2	2019-05-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000704780	SCV002041016	pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002350148	SCV002645928	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-07-01	criteria provided, single submitter	clinical testing	The c.5068+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 38 in the TSC2 gene. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor 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; however, +2T>C alterations are capable of generating wild-type transcripts in some genomic contexts and should be interpreted with caution (Lin JH et al. Hum Mutat. 2019 10;40:1856-1873). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TSC2-related disease (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.