Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000223253 | SCV000274800 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-03-30 | criteria provided, single submitter | clinical testing | The p.V288M variant (also known as c.862G>A), located in coding exon 8 of the NF1 gene, results from a G to A substitution at nucleotide position 862. The valine at codon 288 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 6502 samples (13004 alleles) with coverage at this position. 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.V288Mremains unclear. |
| Invitae | RCV000234015 | SCV000284534 | uncertain significance | Neurofibromatosis, type 1 | 2024-01-05 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 288 of the NF1 protein (p.Val288Met). This variant is present in population databases (rs755670651, gnomAD 0.0009%). 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: 231063). 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. |
| Laboratory for Molecular Medicine, |
RCV000608961 | SCV000731711 | uncertain significance | not specified | 2017-12-14 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. The p.Val288Met var iant in NF1 has been identified by our laboratory in 1 individual with clinical features of RASopathy; however, it was inherited from an unaffected parent. This variant has also been identified in 1/111304 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs755670 651). Computational prediction tools and conservation analysis do not provide st rong support for or against an impact to the protein. In summary, while the clin ical significance of the p.Val288Met variant is uncertain, its identification in an unaffected individual suggests that it is more likely to be benign. ACMG/AMP criteria applied: BS2. |
| Genome- |
RCV000234015 | SCV002561838 | uncertain significance | Neurofibromatosis, type 1 | 2022-03-15 | criteria provided, single submitter | clinical testing |