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

gnomAD frequency: 0.00001  dbSNP: rs876660093

Total submissions: 9

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000632497	SCV000753682	benign	Neurofibromatosis, type 1	2025-01-27	criteria provided, single submitter	clinical testing
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	2024-10-31	criteria provided, single submitter	clinical testing	The NF1 c.4346G>A (p.Ser1449Asn) variant has been reported in the published literature in individuals with breast cancer (PMID: 30287823 (2018)), and in reportedly healthy individuals (PMID: 36243179 (2022), 30287823 (2018)). The frequency of this variant in the general population, 0.00012 (4/33612 chromosomes in Admixed 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 conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Ambry Genetics	RCV004558547	SCV005048172	benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-12-27	criteria provided, single submitter	clinical testing	This alteration is classified as 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.