Submissions for variant NM_001042492.3(NF1):c.7693A>G (p.Thr2565Ala)

dbSNP: rs786202548

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165409	SCV000216136	uncertain significance	Hereditary cancer-predisposing syndrome	2014-08-27	criteria provided, single submitter	clinical testing	The p.T2565A variant (also known as c.7693A>G), located in coding exon 52 of the NF1 gene, results from an A to G substitution at nucleotide position 7693. The threonine at codon 2565 is replaced by alanine, 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.<span style="background-color: initial;">To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 11000 alleles tested) in our clinical cohort. Based on protein sequence alignment, this<span style="background-color: initial;">amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.<span style="background-color: initial;">Since supporting evidence is limited at this time, the clinical significance of p.T2565A remains unclear.
GeneDx	RCV000681135	SCV000808593	uncertain significance	not provided	2018-03-07	criteria provided, single submitter	clinical testing	This variant is denoted NF1 c.7630A>G at the cDNA level, p.Thr2544Ala (T2544A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Thr2544Ala was not observed in large population cohorts (Lek 2016). This variant is located in the C-terminal domain (Luo 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether NF1 Thr2544Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000693796	SCV000821679	uncertain significance	Neurofibromatosis, type 1	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2544 of the NF1 protein (p.Thr2544Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 185904). 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.
Genome-Nilou Lab	RCV000693796	SCV002561119	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478508	SCV002791175	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2021-09-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162700	SCV003896993	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-01-18	criteria provided, single submitter	clinical testing	The p.T2544A variant (also known as c.7630A>G), located in coding exon 51 of the NF1 gene, results from an A to G substitution at nucleotide position 7630. The threonine at codon 2544 is replaced by alanine, an amino acid with similar properties. This alteration was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0001 in 12490 male 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, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.