Submissions for variant NM_000548.5(TSC2):c.3914C>T (p.Pro1305Leu)

gnomAD frequency: 0.00758  dbSNP: rs45517320

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000118705	SCV000169143	benign	not specified	2012-05-11	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000130814	SCV000185710	benign	Hereditary cancer-predisposing syndrome	2014-12-22	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000118705	SCV000205288	benign	not specified	2013-02-21	criteria provided, single submitter	clinical testing	Pro1305Leu in exon 33 of TSC2: This variant is not expected to have clinical sig nificance because it has been identified in 2.1% (91/4368) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs45517320).
Vantari Genetics	RCV000130814	SCV000267098	likely benign	Hereditary cancer-predisposing syndrome	2016-02-04	criteria provided, single submitter	clinical testing
Invitae	RCV000234232	SCV000285373	benign	Tuberous sclerosis 2	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000118705	SCV000305210	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000054866	SCV000395637	likely benign	Tuberous sclerosis syndrome	2018-02-09	criteria provided, single submitter	clinical testing	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000034654	SCV000610914	likely benign	not provided	2017-06-12	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000234232	SCV000677544	benign	Tuberous sclerosis 2	2017-05-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034654	SCV000697466	benign	not provided	2016-08-23	criteria provided, single submitter	clinical testing	Variant summary: The TSC2 c.3914C>T (p.Pro1305Leu) variant causes a missense change involving a non-conserved nucleotide. 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 232/49978 (5 homozygotes, 1/250), predominantly in the African cohort, 220/5384 (1/24), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic TSC2 variant of 1/14534 (0.0000688). Therefore, suggesting the variant is a common benign polymorphism found in population(s) of African origin. In addition, multiple reputable clinical laboratories/databases cite the variant as "likely benign/benign." Therefore, the variant of interest has been classified as Benign.
Genome-Nilou Lab	RCV000234232	SCV002039395	benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034654	SCV003800298	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000234232	SCV004016131	benign	Tuberous sclerosis 2	2023-07-07	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034654	SCV000043537	probably not pathogenic	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Likely benign.
Tuberous sclerosis database (TSC2)	RCV000054866	SCV000066330	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
ITMI	RCV000118705	SCV000086450	not provided	not specified	2013-09-19	no assertion provided	reference population
Genetic Services Laboratory, University of Chicago	RCV000118705	SCV000153120	likely benign	not specified		no assertion criteria provided	clinical testing	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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000118705	SCV001808283	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000118705	SCV001922423	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000118705	SCV001971179	benign	not specified		no assertion criteria provided	clinical testing