Submissions for variant NM_000548.5(TSC2):c.1678G>A (p.Val560Met)

gnomAD frequency: 0.00001  dbSNP: rs141631268

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000562096	SCV000675473	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-05	criteria provided, single submitter	clinical testing	The p.V560M variant (also known as c.1678G>A), located in coding exon 15 of the TSC2 gene, results from a G to A substitution at nucleotide position 1678. The valine at codon 560 is replaced by methionine, an amino acid with highly similar properties. This variant has been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res, 2015 Mar;25:305-15). This alteration was also reported as an incidental finding from one of 1000 participants' exomes and was classified as a Variant of Uncertain Significance (Dorschner MO et al. Am J Hum Genet, 2013 Oct;93:631-40). (Xiong HY et al. Science, 2015 Jan;347:1254806). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080544	SCV000822631	likely benign	Tuberous sclerosis 2	2024-12-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765264	SCV000896517	uncertain significance	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2018-10-31	criteria provided, single submitter	clinical testing
Gharavi Laboratory, Columbia University	RCV000782250	SCV000920740	uncertain significance	not provided	2018-09-16	criteria provided, single submitter	research
Genome-Nilou Lab	RCV001080544	SCV002039568	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000782250	SCV003845501	uncertain significance	not provided	2023-02-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies report this variant is associated with normal TSC2 protein levels, a mild reduction in TSC1 protein levels that did not reach statistical significance, and a mild increase in TORC1 activity that did not reach statistical significance (Hoogeveen-Westerveld et al., 2011); This variant is associated with the following publications: (PMID: 24055113, 21309039, 25525159, 25637381)
Tuberous sclerosis database (TSC2)	RCV000055282	SCV000083502	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
CSER _CC_NCGL, University of Washington	RCV000055282	SCV000190667	uncertain significance	Tuberous sclerosis syndrome	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000782250	SCV001549038	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TSC2 p.V560M variant was not identified in the literature but was identified in dbSNP (ID: rs141631268) and ClinVar (classified as uncertain significance by Fulgent Genetics, Ambry Genetics and two other submitters; and as likely benign by Invitae). The variant was identified in control databases in 3 of 250734 chromosomes at a frequency of 0.00001196 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.V560 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.