Submissions for variant NM_001042492.3(NF1):c.2054C>G (p.Thr685Ser)

gnomAD frequency: 0.00001  dbSNP: rs876658190

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216178	SCV000273112	uncertain significance	Hereditary cancer-predisposing syndrome	2015-01-20	criteria provided, single submitter	clinical testing	The p.T685S variant (also known as c.2054C>G), located in coding exon 18 of the NF1 gene, results from a C to G substitution at nucleotide position 2054. The threonine at codon 685 is replaced by serine, an amino acid with similar 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. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 30,000 alleles tested) in our clinical cohort.This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Since supporting evidence is limited at this time, the clinical significance of p.T685Sremains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233280	SCV000284402	likely benign	Neurofibromatosis, type 1	2024-12-20	criteria provided, single submitter	clinical testing
GeneDx	RCV002222446	SCV002499883	uncertain significance	not provided	2022-04-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25486365)
Genome-Nilou Lab	RCV000233280	SCV002561990	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478783	SCV002785469	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2022-03-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558469	SCV005047592	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-02-12	criteria provided, single submitter	clinical testing	The c.2054C>G (p.T685S) alteration is located in exon 18 (coding exon 18) of the NF1 gene. This alteration results from a C to G substitution at nucleotide position 2054, causing the threonine (T) at amino acid position 685 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000233280	SCV005689163	uncertain significance	Neurofibromatosis, type 1	2024-08-14	criteria provided, single submitter	clinical testing	The NF1 c.2054C>G (p.Thr685Ser) missense change has a maximum subpopulation frequency of 0.002% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but this prediction has not been confirmed by functional studies. 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.