Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002434403 | SCV001189237 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2018-12-26 | criteria provided, single submitter | clinical testing | The p.E2587Q variant (also known as c.7759G>C), located in coding exon 52 of the NF1 gene, results from a G to C substitution at nucleotide position 7759. The glutamic acid at codon 2587 is replaced by glutamine, an amino acid with highly similar properties. This alteration was observed with an allele frequency of 0.00071 in 7051 unselected female breast cancer patients and with an allele frequency of 0.00053 in 11241 female controls of Japanese ancestry. It was also was observed with an allele frequency of 0.0000 in 53 unselected male breast cancer patients and with an allele frequency of 0.0002 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, 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001824915 | SCV002074492 | uncertain significance | not specified | 2022-01-31 | criteria provided, single submitter | clinical testing | Variant summary: NF1 c.7759G>C (p.Glu2587Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-05 in 298608 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 (5.7e-05 vs 0.00021), allowing no conclusion about variant significance. c.7759G>C has been reported in the literature in individuals affected with breast cancer as well as in controls (Momozawa_2018). The report does not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Labcorp Genetics |
RCV002552417 | SCV003473271 | uncertain significance | Neurofibromatosis, type 1 | 2024-10-09 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 2587 of the NF1 protein (p.Glu2587Gln). 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: 827243). 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) 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. |