Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM5BP4BP6BS2
The NM_000548.5(TSC2):c.4225C>T(p.Arg1409Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,609,208 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. R1409G) 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 -4 ACMG points.
PM5
?
PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr16-2084447-C-G is described in Lovd as [Likely_pathogenic].
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.4073082).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 16-2084447-C-T is Benign according to our data. Variant chr16-2084447-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41740.We mark this variant Likely_benign, oryginal submissions are: {not_provided=2, Likely_benign=6, Benign=3, Uncertain_significance=2}. Variant chr16-2084447-C-T is described in Lovd as [Benign]. Variant chr16-2084447-C-T is described in Lovd as [Likely_benign].
BS2
?
BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
Likely benign, criteria provided, single submitter
clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Jan 24, 2023
- -
Likely benign, no assertion criteria provided
research
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Jul 13, 2012
- -
Uncertain significance, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Aug 27, 2014
- -
Likely benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Feb 01, 2023
TSC2: BS2 -
Tuberous sclerosis 2 Benign:2Other:1
Benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Nov 07, 2021
- -
not provided, no classification provided
phenotyping only
GenomeConnect - Invitae Patient Insights Network
-
Variant interpreted as Benign and reported on 05-23-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Benign, criteria provided, single submitter
clinical testing
Invitae
Jan 28, 2024
- -
not specified Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Feb 25, 2020
Variant summary: TSC2 c.4225C>T (p.Arg1409Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-05 in 239990 control chromosomes, predominantly at a frequency of 0.0001 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.4225C>T has been reported in the literature in at least one individual affected with Tuberous Sclerosis Complex (Zarei_2002). This report does not provide unequivocal conclusions about association of the variant with Tuberous Sclerosis Complex. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Hoogeveen-Westerveld_2011). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign n=3; VUS n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter
clinical testing
GeneDx
Apr 25, 2017
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter
curation
Sema4, Sema4
Feb 03, 2021
- -
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Mar 04, 2019
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Mar 30, 2021
TSC2 NM_000548 exon 34 p.Arg1409Trp (c.4225C>T): This variant has not been reported in the literature but is present in 11/121418 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs45517333). This variant is present in ClinVar, with several labs classifying this variant as likely benign or benign (Variation ID: 41740). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
TSC2-related disorder Benign:1
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Mar 15, 2023
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -