Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000548.5(TSC2):c.2032G>A(p.Ala678Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000376 in 1,593,938 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A678D) 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=0.00718987).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 16-2071869-G-A is Benign according to our data. Variant chr16-2071869-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 184135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071869-G-A is described in Lovd as [Likely_benign]. Variant chr16-2071869-G-A is described in Lovd as [Benign]. Variant chr16-2071869-G-A is described in Lovd as [Pathogenic].
BS1
?
BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000663 (101/152338) while in subpopulation EAS AF= 0.0128 (66/5174). AF 95% confidence interval is 0.0103. There are 1 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
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
Quest Diagnostics Nichols Institute San Juan Capistrano
Jun 02, 2020
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Benign, criteria provided, single submitter
clinical testing
GeneDx
Sep 15, 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. -
Benign, criteria provided, single submitter
clinical testing
Athena Diagnostics
Jun 02, 2020
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Likely benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Feb 04, 2024
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Tuberous sclerosis 2 Benign:4
Benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Nov 07, 2021
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Benign, criteria provided, single submitter
clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Jul 07, 2023
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Benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Aug 31, 2022
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Benign, criteria provided, single submitter
clinical testing
Invitae
Feb 01, 2024
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not provided Benign:4
Likely benign, no assertion criteria provided
clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
-
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Likely benign, no assertion criteria provided
clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
-
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Likely benign, no assertion criteria provided
clinical testing
Clinical Genetics, Academic Medical Center
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Benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Apr 01, 2023
TSC2: BP4, BS1, BS2 -
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter
curation
Sema4, Sema4
Dec 26, 2020
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Benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Sep 28, 2015
This alteration is classified as 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. -
Tuberous sclerosis syndrome Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Sep 12, 2018
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
TSC2-related disorder Benign:1
Benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
May 02, 2019
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -