Submissions for variant NM_001042492.3(NF1):c.2002-4_2002-3del

dbSNP: rs786203664

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167074	SCV000217902	uncertain significance	Hereditary cancer-predisposing syndrome	2015-08-10	criteria provided, single submitter	clinical testing	<p style="text-align:justify">The c.2002-4_2002-3delTC intronic variant is located three nucleotides before coding exon 18 of the NF1 gene. This variant results from a deletion of twonucleotides at positionsc.2002-3 andc.2002-4.Based on data from the NHLBI Exome Sequencing Project(ESP), thisallele has an overall frequency of approximately 0.01% (1/12518) total alleles studied and 0.01% (1/8254) EuropeanAmerican alleles.Allele frequency datafor this varaint are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single NucleotidePolymorphisms (dbSNP). To date, this alteration has been detected with an allele frequency of approximately 0.003% (>30000 alleles tested) in our clinical cohort.Thesenucleotide positions arenot well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the nativesplice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of c.2002-4_2002-3delTC remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476620	SCV000542021	likely benign	Neurofibromatosis, type 1	2025-01-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001753570	SCV002006080	uncertain significance	not provided	2019-07-08	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Genetic Services Laboratory, University of Chicago	RCV001818397	SCV002065271	uncertain significance	not specified	2021-05-14	criteria provided, single submitter	clinical testing	DNA sequence analysis of the NF1 gene demonstrated a two-nucleotide deletion in intron 17, c.2002-4_2002-3del. This change does not appear to have been previously described in individuals with NF1-related disorders, however, a sequence change at a similar position (c.2002-3C>G) has been described in one family with spinal neurofibromatosis (PMID: 23812910). The c.2002-4_2002-3del sequence change has been described in one non-Finnish European the gnomAD population database (dbSNP rs1363607538). This sequence change is not clearly predicted to have a deleterious effect on splicing based on in silico splice prediction programs. It is possible that this sequence change represents a benign sequence change in the NF1 gene that has not been identified to date. The functional significance of this sequence change is not known at present and its contribution to this patient's disease phenotype cannot definitively be determined.
Ambry Genetics	RCV002415713	SCV002721698	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-02-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000476620	SCV005689164	uncertain significance	Neurofibromatosis, type 1	2024-08-14	criteria provided, single submitter	clinical testing	The NF1 c.2002-4_2002-3del intronic change results in a deletion of two nucleotides at the -4 and -3 position of intron 17 of the NF1 gene. Algorithms that predict the impact of sequence changes on splicing indicate that this variant likely does not affect splicing. This variant has a maximum subpopulation frequency of 0.0009% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). This variant has not been reported in individuals with neurofibromatosis type 1. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.