Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_000548.5(TSC2):c.167A>G(p.Asn56Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000459 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict 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. N56I) has been classified as Uncertain significance.
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]
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=0.17656234).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 16-2050428-A-G is Benign according to our data. Variant chr16-2050428-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161398.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=3, Likely_pathogenic=1}. Variant chr16-2050428-A-G is described in Lovd as [Likely_pathogenic]. Variant chr16-2050428-A-G is described in Lovd as [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
curation
Sema4, Sema4
Sep 05, 2021
- -
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Sep 11, 2018
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. -
Ovarian cancer Pathogenic:1
Likely pathogenic, criteria provided, single submitter
clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University
Jan 01, 2022
- -
Tuberous sclerosis syndrome Uncertain:1
Uncertain significance, no assertion criteria provided
research
CSER _CC_NCGL, University of Washington
Jun 01, 2014
- -
TSC2-related disorder Benign:1
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Nov 01, 2022
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). -
not provided Benign:1
Benign, criteria provided, single submitter
clinical testing
GeneDx
May 20, 2019
This variant is associated with the following publications: (PMID: 30564305, 18386375, 25637381) -