Submissions for variant NM_001042492.3(NF1):c.4409G>A (p.Ser1470Asn)

gnomAD frequency: 0.00001  dbSNP: rs876660093

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222235	SCV000277224	uncertain significance	Hereditary cancer-predisposing syndrome	2015-07-15	criteria provided, single submitter	clinical testing	The p.S1470N variant (also known as c.4409G>A), located in coding exon 33 of the NF1 gene, results from a G to A substitution at nucleotide position 4409. The serine at codon 1470 is replaced by asparagine, an amino acid with highly 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 6497 samples (12994 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 110000 alleles tested) in our clinical cohort.This amino acid position is well conserved in available vertebrate species, however asparagine is the reference amino acid in several 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.S1470N remains unclear.
Invitae	RCV000632497	SCV000753682	uncertain significance	Neurofibromatosis, type 1	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1449 of the NF1 protein (p.Ser1449Asn). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 232946). 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.
Fulgent Genetics, Fulgent Genetics	RCV000764112	SCV000895080	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
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030575	SCV001193665	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Baylor Genetics	RCV000632497	SCV001482854	uncertain significance	Neurofibromatosis, type 1	2020-12-04	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731450	SCV001983440	uncertain significance	not specified	2021-09-11	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.4346G>A (p.Ser1449Asn) results in a conservative amino acid change located in the Ras GTPase-activating domain (IPR001936) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 236450 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4346G>A has been reported in the literature as a VUS in settings of multigene panel testing of Japanese individuals affected with breast cancer as well as in unaffected Japanese controls (example, Momozawa_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000632497	SCV002560420	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002478807	SCV002774828	uncertain significance	not provided	2022-07-10	criteria provided, single submitter	clinical testing