Submissions for variant NM_001042492.3(NF1):c.8494C>T (p.Arg2832Cys)

gnomAD frequency: 0.00002  dbSNP: rs587782893

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132532	SCV000187629	uncertain significance	Hereditary cancer-predisposing syndrome	2015-08-28	criteria provided, single submitter	clinical testing	The p.R2832C variant (also known as c.8494C>T), located in coding exon 58 of the NF1 gene, results from a C to T substitution at nucleotide position 8494. The arginine at codon 2832 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project.To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 55000 alleles tested) in our clinical cohort.This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of p.R2832C remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546661	SCV000628820	likely benign	Neurofibromatosis, type 1	2024-12-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132532	SCV002528153	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-13	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000546661	SCV002561528	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162595	SCV003897015	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-12-06	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.
GeneDx	RCV003162594	SCV003914867	uncertain significance	not provided	2022-10-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer (Abdel-Razeq et al., 2022); This variant is associated with the following publications: (PMID: 25486365, 35402282)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003162594	SCV005624673	uncertain significance	not provided	2024-12-02	criteria provided, single submitter	clinical testing	The NF1 c.8431C>T (p.Arg2811Cys) variant has been reported in the published literature in an individual with breast cancer (PMID: 35402282 (2022)) and a pediatric case of rhabdosarcoma (PMID: 26580448 (2015)). This variant has also been identified in a reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.00012 (3/24960 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.