Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000548.5(TSC2):āc.5321G>Cā(p.Ser1774Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,612,806 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1774G) 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]
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=0.0038832724).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 16-2088507-G-C is Benign according to our data. Variant chr16-2088507-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 41745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088507-G-C is described in Lovd as [Benign]. Variant chr16-2088507-G-C is described in Lovd as [Pathogenic].
BS1
?
BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00886 (1350/152300) while in subpopulation AFR AF= 0.0305 (1268/41552). AF 95% confidence interval is 0.0291. There are 29 homozygotes in gnomad4. There are 639 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jun 16, 2017
Variant summary: The TSC2 c.5321G>C (p.Ser1774Thr) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 359/119808 control chromosomes (6 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.033497 (342/10210). This frequency is about 487 times the estimated maximal expected allele frequency of a pathogenic TSC2 variant (0.0000688), strong evidence that this is a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, no assertion criteria provided
research
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Jul 13, 2012
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Benign, criteria provided, single submitter
clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Jun 19, 2020
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Likely benign, criteria provided, single submitter
clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Aug 19, 2015
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Benign, criteria provided, single submitter
clinical testing
GeneDx
Mar 03, 2015
This variant is associated with the following publications: (PMID: 24728327, 17304050, 22903760) -
Benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
May 01, 2024
TSC2: BP4, BS1, BS2 -
not specified Benign:5Other:1
Benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
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not provided, no classification provided
reference population
ITMI
Sep 19, 2013
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Benign, criteria provided, single submitter
clinical testing
Eurofins Ntd Llc (ga)
Apr 02, 2015
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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
Genetic Services Laboratory, University of Chicago
-
Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided
clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center
-
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Tuberous sclerosis 2 Benign:3
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
Invitae
Feb 01, 2024
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Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter
curation
Sema4, Sema4
Sep 10, 2020
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Benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Apr 06, 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:1Other:1
Benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Jan 13, 2018
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided, no classification provided
curation
Tuberous sclerosis database (TSC2)
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Polycystic kidney disease, adult type Benign:1
Likely benign, criteria provided, single submitter