Submissions for variant NM_000548.5(TSC2):c.1933G>A (p.Val645Ile)

dbSNP: rs746677177

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000467991	SCV000544396	benign	Tuberous sclerosis 2	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000603190	SCV000726488	likely benign	not specified	2018-01-08	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.
Genome-Nilou Lab	RCV000467991	SCV002041407	benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002411434	SCV002720774	likely benign	Hereditary cancer-predisposing syndrome	2020-05-05	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000603190	SCV004122012	uncertain significance	not specified	2023-10-03	criteria provided, single submitter	clinical testing	Variant summary: TSC2 c.1933G>A (p.Val645Ile) results in a conservative amino acid change located in the Tuberin-type domain (IPR018515) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250264 control chromosomes, predominantly at a frequency of 0.00012 within the Latino subpopulation in the gnomAD database. While the frequency of the variant in the Latino subpopulation is higher than expected for a pathogenic variant, clear conclusions cannot be drawn due to the small number of variant occurrences (4/34554). To our knowledge, no occurrence of c.1933G>A in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as benign (n=2) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CeGaT Center for Human Genetics Tuebingen	RCV003392273	SCV004133824	likely benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	TSC2: BP4
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003392273	SCV004221410	uncertain significance	not provided	2012-02-23	criteria provided, single submitter	clinical testing