Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_ModerateBP6BS2
The NM_000548.5(TSC2):āc.4362T>Gā(p.Ser1454Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,453,932 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1454G) has been classified as Likely benign.
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 Likely_benign. Variant got -5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13756165).
BP6
Variant 16-2084584-T-G is Benign according to our data. Variant chr16-2084584-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 535857.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=2}.
Review Status: criteria provided, single submitter
Collection Method: curation
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Aug 07, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.S1454R variant (also known as c.4362T>G), located in coding exon 33 of the TSC2 gene, results from a T to G substitution at nucleotide position 4362. The serine at codon 1454 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Tuberous sclerosis 2 Benign:1
Dec 18, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Ovarian cancer Benign:1
Jan 01, 2022
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University
Significance: Benign
Review Status: criteria provided, single submitter