Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000548.5(TSC2):c.1362-10C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Uncertain significance, criteria provided, single submitter
research
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Nov 30, 2021
ACMG codes: PM2, PP3 -
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Dec 29, 2023
This sequence change falls in intron 13 of the TSC2 gene. It does not directly change the encoded amino acid sequence of the TSC2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with tuberous sclerosis complex (PMID: 26540169; Invitae). ClinVar contains an entry for this variant (Variation ID: 50185). Studies have shown that this variant is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -
The c.1362-10C>A intronic pathogenic mutation results from a C to A substitution 10 nucleotides upstream from coding exon 13 in the TSC2 gene. This alteration has been observed in many individuals with a personal and/or family history that is consistent with TSC2-related disease (Ambry internal data; Personal communication; Tyburczy ME et al. PLoS Genet, 2015 Nov;11:e1005637; Choy YS et al. Ann Hum Genet, 1999 Sep;63:383-91). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Aug 10, 2023
Reported as a benign variant in published literature; however, additional information was not provided (Au et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as IVS12-10C>A; This variant is associated with the following publications: (PMID: 26540169, 10735580, 17304050) -
TSC2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
May 10, 2023
The TSC2 c.1362-10C>A variant is predicted to interfere with splicing. The c.1362-10 C>A intronic variant in the TSC2 gene has been reported in individuals affected with tuberous sclerosis, and has been reported to segregate with affected status within a family; however, minimal details were provided (Tyburczy et al. 2015. PubMed ID: 26540169; Choy et al. 1999. PubMed ID: 10735580; Au et al. 2007. PubMed ID: 17304050; https://databases.lovd.nl/shared/variants/TSC2). This variant is predicted to abolish the canonical splice acceptor site based on available splicing prediction programs (Alamut Visual Plus v1.6.1). However, the use of computer prediction programs is not equivalent to functional evidence. In ClinVar this variant has conflicting classifications including pathogenic, likely pathogenic, uncertain significance, and benign (https://preview.ncbi.nlm.nih.gov/clinvar/variation/50185/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Isolated focal cortical dysplasia type II Uncertain:1
Uncertain significance, criteria provided, single submitter