Submissions for variant NM_000548.5(TSC2):c.3915G>A (p.Pro1305=)

gnomAD frequency: 0.02216  dbSNP: rs11551373

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000118706	SCV000169144	benign	not specified	2012-05-24	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	RCV000129645	SCV000184440	benign	Hereditary cancer-predisposing syndrome	2014-11-30	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	RCV000118706	SCV000269920	benign	not specified	2013-02-21	criteria provided, single submitter	clinical testing	Pro1305Pro in exon 33 of TSC2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 6.6% (290/4372) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs11551373).
PreventionGenetics, part of Exact Sciences	RCV000118706	SCV000305211	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000042539	SCV000395638	benign	Tuberous sclerosis syndrome	2018-01-13	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000470595	SCV000556687	benign	Tuberous sclerosis 2	2024-02-01	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000470595	SCV000677545	benign	Tuberous sclerosis 2	2017-05-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587118	SCV000697467	benign	not provided	2016-08-23	criteria provided, single submitter	clinical testing	Variant summary: The TSC2 c.3915G>A (p.Pro1305Pro) variant causes a synonymous change involving a non-conserved nucleotide with 4/5 splice prediction tools predicting no significant impact on splicing or ESE binding, 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 536/51912 (14 homozygotes, 1/96), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic TSC2 variant of 1/14534 (0.0000688), suggesting this variant is likely a benign polymorphism. In addition, multiple reputable clinical laboratories/databases cite the variant as "benign/likely benign." Therefore, the variant of interest has been classified as Benign.
Genome-Nilou Lab	RCV000470595	SCV002039396	benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490590	SCV002804372	benign	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2021-07-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587118	SCV003800386	benign	not provided	2023-08-02	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000470595	SCV004016123	benign	Tuberous sclerosis 2	2023-07-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000470595	SCV004360909	benign	Tuberous sclerosis 2	2019-03-29	criteria provided, single submitter	clinical testing
Tuberous sclerosis database (TSC2)	RCV000042539	SCV000066331	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Genetic Services Laboratory, University of Chicago	RCV000118706	SCV000153121	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	RCV000118706	SCV001808336	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000118706	SCV001925654	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000118706	SCV001975758	benign	not specified		no assertion criteria provided	clinical testing