Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000215281 | SCV000275565 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-12-13 | criteria provided, single submitter | clinical testing | The p.I2746M variant (also known as c.8238T>G), located in coding exon 57 of the NF1 gene, results from a T to G substitution at nucleotide position 8238. The isoleucine at codon 2746 is replaced by methionine, 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 well 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 p.I2746M remains unclear. |
| Invitae | RCV000230134 | SCV000284524 | uncertain significance | Neurofibromatosis, type 1 | 2024-01-08 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2725 of the NF1 protein (p.Ile2725Met). This variant is present in population databases (rs779789452, gnomAD 0.002%). 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: 231655). 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. |
| Johns Hopkins Genomics, |
RCV000230134 | SCV001548495 | uncertain significance | Neurofibromatosis, type 1 | 2021-04-01 | criteria provided, single submitter | clinical testing | NF1 c.8238T>G (rs779789452) is rare (<0.1%) in a large population dataset (gnomAD: 2/251440 total alleles; 0.0008%; no homozygotes) and has not been reported in the literature, to our knowledge. This variant has been reported in ClinVar (Variation ID: 231655). Three bioinformatic tools queried predict that this substitution would be tolerated, however the isoleucine residue at this position is evolutionarily conserved across most species assessed. We consider the clinical significance of NF1 c.8238T>G to be uncertain at this time. |
| Genome- |
RCV000230134 | SCV002561191 | uncertain significance | Neurofibromatosis, type 1 | 2022-03-15 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV002494592 | SCV002784192 | uncertain significance | Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis | 2021-08-18 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV003165564 | SCV003895041 | likely benign | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-01-04 | 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. |