Submissions for variant NM_001042492.3(NF1):c.8407C>A (p.Pro2803Thr)

dbSNP: rs779180729

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227147	SCV000284529	uncertain significance	Neurofibromatosis, type 1	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2782 of the NF1 protein (p.Pro2782Thr). This variant is present in population databases (rs779180729, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 237607). Invitae Evidence 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 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.
Ambry Genetics	RCV002338704	SCV001178684	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-10-15	criteria provided, single submitter	clinical testing	The p.P2782T variant (also known as c.8344C>A), located in coding exon 57 of the NF1 gene, results from a C to A substitution at nucleotide position 8344. The proline at codon 2782 is replaced by threonine, an amino acid with highly similar properties. This alteration has been reported with a carrier frequency of 0.00085 in 7051 unselected breast cancer patients and 0.00053 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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 of this alteration remains unclear.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030642	SCV001193672	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Genome-Nilou Lab	RCV000227147	SCV002561520	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing