Submissions for variant NM_001042492.3(NF1):c.4766C>T (p.Thr1589Met)

gnomAD frequency: 0.00001  dbSNP: rs185660700

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000195487	SCV000254503	uncertain significance	Neurofibromatosis, type 1	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1568 of the NF1 protein (p.Thr1568Met). This variant is present in population databases (rs185660700, gnomAD 0.01%). 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: 216405). 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 expected to disrupt 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	RCV000213390	SCV000275473	uncertain significance	Hereditary cancer-predisposing syndrome	2015-12-10	criteria provided, single submitter	clinical testing	The p.T1589M variant (also known as c.4766C>T), located in coding exon 36 of the NF1 gene, results from a C to T substitution at nucleotide position 4766. The threonine at codon 1589 is replaced by methionine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs185660700. Based on data from the 1000 Genomes Project, the T allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.94% (1/106) African-American SW alleles. This variant was not reported in the NHLBI Exome Sequencing Project (ESP) population-based cohort.To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 110000alleles tested) in our clinical cohort.This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of p.T1589Mremains unclear.
PreventionGenetics, part of Exact Sciences	RCV000679395	SCV000806286	uncertain significance	not provided	2017-05-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000679395	SCV000808483	uncertain significance	not provided	2022-11-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with breast cancer (Momozawa 2018); This variant is associated with the following publications: (PMID: 30287823)
Fulgent Genetics, Fulgent Genetics	RCV000764113	SCV000895081	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2022-05-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000213390	SCV002527584	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-21	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000195487	SCV002560464	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003165467	SCV003899271	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-01-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679395	SCV004565108	uncertain significance	not provided	2023-05-03	criteria provided, single submitter	clinical testing	The NF1 c.4766C>T; p.Thr1589Met variant (rs185660700), is reported in the literature in individuals affected with breast cancer but is also found in controls (Momozawa 2018). This variant is reported in ClinVar (Variation ID: 216405) and is found in the general population with an overall allele frequency of 0.0025% (7/282,338 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.318). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. PMID: 30287823.