Submissions for variant NM_001042492.3(NF1):c.2747A>G (p.Asn916Ser)

gnomAD frequency: 0.00003  dbSNP: rs765043916

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220288	SCV000273368	uncertain significance	Hereditary cancer-predisposing syndrome	2015-08-22	criteria provided, single submitter	clinical testing	Thep.N916Svariant (also known as c.2747A>G), located in coding exon 21 of theNF1gene, results from an A to G substitution at nucleotide position 2747. The asparagine at codon 916 is replaced by serine, 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 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 110000 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.N916S remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226024	SCV000284420	uncertain significance	Neurofibromatosis, type 1	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 916 of the NF1 protein (p.Asn916Ser). This variant is present in population databases (rs765043916, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 29290338). ClinVar contains an entry for this variant (Variation ID: 229977). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. 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.
PreventionGenetics, part of Exact Sciences	RCV000679381	SCV000806268	uncertain significance	not provided	2016-11-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000679381	SCV000808688	uncertain significance	not provided	2023-02-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an infant with less than 5 cafe-au-lait macules and a CNS glioma, and was also observed to segregate with cafe-au-lait macules in three affected family members in another kindred (Koczkowska et al., 2018); Observed in both cases and controls in a breast cancer case-control study (Dorling et al., 2021); This variant is associated with the following publications: (PMID: 24030381, 25486365, 2121369, 33471991, 29290338)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761186	SCV000891102	uncertain significance	Acute monocytic leukemia; Acute monoblastic leukemia	2017-04-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818516	SCV002071564	uncertain significance	not specified	2019-08-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000220288	SCV002527475	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-18	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000226024	SCV002562088	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558475	SCV005047610	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-06-16	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.