Submissions for variant NM_000548.5(TSC2):c.1609C>T (p.Arg537Cys)

gnomAD frequency: 0.00054  dbSNP: rs142257684

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000231616	SCV000285252	benign	Tuberous sclerosis 2	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001703957	SCV000528132	benign	not provided	2020-11-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23514105, 21624971, 28407358, 28250423, 30564305)
Ambry Genetics	RCV000564084	SCV000675476	likely benign	Hereditary cancer-predisposing syndrome	2018-09-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000431368	SCV000711363	likely benign	not specified	2019-08-28	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000431368	SCV001737708	benign	not specified	2021-05-30	criteria provided, single submitter	clinical testing	Variant summary: TSC2 c.1609C>T (p.Arg537Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 250188 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), strongly suggesting that the variant is benign. Although this variant has been reported in the literature, to our knowledge, no occurrence of c.1609C>T in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=1)/likely benign (n=3). Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV000231616	SCV002041358	benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000564084	SCV002530972	likely benign	Hereditary cancer-predisposing syndrome	2021-06-03	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001703957	SCV004221406	uncertain significance	not provided	2014-09-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905018	SCV004732926	likely benign	TSC2-related condition	2022-09-13	criteria provided, single submitter	clinical testing	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).
Tuberous sclerosis database (TSC2)	RCV000055179	SCV000083397	not provided	Tuberous sclerosis syndrome		no assertion provided	curation