Submissions for variant NM_000548.5(TSC2):c.5262C>G (p.Ile1754Met)

gnomAD frequency: 0.00025  dbSNP: rs397515318

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001086420	SCV000544479	benign	Tuberous sclerosis 2	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000572414	SCV000664736	benign	Hereditary cancer-predisposing syndrome	2020-11-02	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589806	SCV000697477	uncertain significance	not provided	2017-06-16	criteria provided, single submitter	clinical testing	Variant summary: The TSC2 c.5262C>G (p.Ile1754Met) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant. This variant was found in 6/119900 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.000586 (6/10236). This frequency is about 9 times the estimated maximal expected allele frequency of a pathogenic TSC2 variant (0.0000688), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance - possibly benign variant until additional information becomes available.
GeneDx	RCV000589806	SCV001935518	benign	not provided	2019-02-12	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001086420	SCV002040268	benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000572414	SCV002534043	benign	Hereditary cancer-predisposing syndrome	2020-11-29	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000589806	SCV001549120	likely benign	not provided		no assertion criteria provided	clinical testing	The TSC2 p.Ile1651Met variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs397515318) and in ClinVar (alias: NM_000548.4:c.5262C>G (p.Ile1754Met); classified as conflicting interpretations of pathogenicity with benign by Invitae and VUS by Ambry Genetics and Integrated Genetics; associated conditions are Tuberous sclerosis 2 and Hereditary cancer-predisposing syndrome) The variant was identified in control databases in 21 of 281550 chromosomes at a frequency of 0.000075 (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: African in 19 of 24858 chromosomes (freq: 0.000764), Latino in 1 of 35422 chromosomes (freq: 0.000028) and European (non-Finnish) in 1 of 128140 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other and South Asian populations. The p.Ile1651 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Ile1651Met variant occurs in the first three bases of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.