Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000217495 | SCV000278760 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-10-06 | criteria provided, single submitter | clinical testing | The p.P2567L variant (also known as c.7700C>T), located in coding exon 52 of the NF1 gene, results from a C to T substitution at nucleotide position 7700. The proline at codon 2567 is replaced by leucine, an amino acid with somewhat 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 X.002% (greater than 55000alleles tested) in our clinical cohort.This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and yet tolerated by PolyPhen and SIFT in silico analyses, respectively.Since supporting evidence is limited at this time, the clinical significance of pP2567Lremains unclear. |
| Center for Human Genetics, |
RCV000660118 | SCV000782108 | likely pathogenic | Neurofibromatosis, type 1 | 2016-11-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000660118 | SCV000836245 | uncertain significance | Neurofibromatosis, type 1 | 2019-09-27 | criteria provided, single submitter | clinical testing | This sequence change replaces proline with leucine at codon 2546 of the NF1 protein (p.Pro2546Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 234225). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. |