Submissions for variant NM_001042492.3(NF1):c.7891A>G (p.Thr2631Ala)

gnomAD frequency: 0.00001  dbSNP: rs199474793

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222408	SCV000273712	uncertain significance	Hereditary cancer-predisposing syndrome	2015-02-04	criteria provided, single submitter	clinical testing	The p.T2631A variant (also known as c.7891A>G or p.T2610A or c.7828A>G), located in coding exon 54 of the NF1 gene, results from an A to G substitution at nucleotide position 7891. The threonine at codon 2631 is replaced by alanine, an amino acid with similar properties. This alteration has beendetected in an individual with a clinical diagnosis of neurofibromatosis type 1 (NF1) (Upadhyaya M,J. Med. Genet. 1995 Sep; 32(9):706-10).This variant was previously reported in the SNPDatabase as rs199474793. This variant was not reported in population-based cohorts in the following databases:NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project.To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 30000alleles tested) in our clinical cohort.This amino acid position is well 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.T2631Aremains unclear.
Invitae	RCV000234372	SCV000284517	uncertain significance	Neurofibromatosis, type 1	2024-01-16	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 2610 of the NF1 protein (p.Thr2610Ala). This variant is present in population databases (rs199474793, gnomAD 0.002%). This missense change has been observed in individual(s) with multiple endocrine neoplasia, type 2A and/or neurofibromatosis type I (PMID: 8544190, 24694336). This variant is also known as c.7891A>G (p.Thr2631Ala). ClinVar contains an entry for this variant (Variation ID: 68363). 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 not expected to disrupt NF1 protein function with a negative predictive value of 95%. 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.
Fulgent Genetics, Fulgent Genetics	RCV000764118	SCV000895086	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2021-11-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000059217	SCV001787318	uncertain significance	not provided	2022-08-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a patient with cutaneous features of neurofibromatosis type 1 (Upadhyaya et al., 1995); This variant is associated with the following publications: (PMID: 24694336, 34426522, 25486365, 8544190)
Genome-Nilou Lab	RCV000234372	SCV002561155	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Medical Genetics, University of Parma	RCV000234372	SCV002567768	uncertain significance	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000059217	SCV003815867	uncertain significance	not provided	2022-08-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162465	SCV003897004	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-02-01	criteria provided, single submitter	clinical testing	The p.T2610A variant (also known as c.7828A>G), located in coding exon 53 of the NF1 gene, results from an A to G substitution at nucleotide position 7828. The threonine at codon 2610 is replaced by alanine, an amino acid with similar properties. This alteration has been detected in an individual with a clinical diagnosis of neurofibromatosis type 1 (NF1) (Upadhyaya M, J. Med. Genet. 1995 Sep; 32(9):706-10). This variant was also reported in 3/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant has been detected in multiple individuals with no reported NF1-associated features (Ambry internal data). This amino acid position is well 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.
Baylor Genetics	RCV003460655	SCV004198254	uncertain significance	Juvenile myelomonocytic leukemia	2023-10-17	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000234372	SCV004812506	uncertain significance	Neurofibromatosis, type 1	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change in NF1 is predicted to replace threonine with alanine at codon 2631, p.(Thr2631Ala). The threonine residue is highly conserved (92/95 vertebrates, UCSC), and is not located in an annotated domain. There is a small physicochemical difference between threonine and alanine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.002% (2/113,630 alleles) in the European (non-Finnish) population. This variant has been reported in at least one proband with sporadic neurofibromatosis type 1 and an individual with pheochromocytoma explained by a pathogenic variant in RET (PMID: 8544190, 24694336). The prevalence of the variant in individuals with breast cancer is not significantly increased compared with the prevalence in controls (PMID: 33471991). Computational evidence predicts a benign effect for the missense substitution (REVEL = 0.279). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: BP4.
UniProtKB/Swiss-Prot	RCV000059217	SCV000090746	not provided	not provided		no assertion provided	not provided