Submissions for variant NM_001042492.3(NF1):c.2585C>G (p.Thr862Ser)

gnomAD frequency: 0.00003  dbSNP: rs200302954

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000200298	SCV000254491	uncertain significance	Neurofibromatosis, type 1	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 862 of the NF1 protein (p.Thr862Ser). This variant is present in population databases (rs200302954, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 23656349, 31159747). ClinVar contains an entry for this variant (Variation ID: 41670). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NF1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000222839	SCV000273921	uncertain significance	Hereditary cancer-predisposing syndrome	2015-09-08	criteria provided, single submitter	clinical testing	Thep.T862Svariant (also known as c.2585C>G), located in coding exon 21 of theNF1gene, results from a C to G substitution at nucleotide position 2585. The threonine at codon 862 is replaced by serine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs200302954, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases.To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 110000 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 ofp.T862Sremains unclear.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000034582	SCV000511772	uncertain significance	not provided	2017-02-08	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV000034582	SCV000806267	uncertain significance	not provided	2017-09-08	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000222839	SCV000822093	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765346	SCV000896610	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000034582	SCV002008433	uncertain significance	not provided	2023-05-09	criteria provided, single submitter	clinical testing	Reported previously as a variant of uncertain significance in a patient with a personal or family history of breast and/or ovarian cancer in published literature; however, clinical and segregation information was not provided (Tsaousis et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23656349, 22703879, 29290338, 31159747, 30308447, 25486365, 2121369)
Genome-Nilou Lab	RCV000200298	SCV002562064	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000200298	SCV002579916	uncertain significance	Neurofibromatosis, type 1	2022-05-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426541	SCV002743957	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-02-28	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.
CeGaT Center for Human Genetics Tuebingen	RCV000034582	SCV004142538	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	NF1: BP4
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034582	SCV000043388	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000034582	SCV001741681	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000034582	SCV001967479	uncertain significance	not provided		no assertion criteria provided	clinical testing