ClinVar Genomic variation as it relates to human health

The NF1 c.983_984delGT; p.Cys328Ter variant (rs1555610893) is reported in the literature in several individuals affected with neurofibromatosis type 1 (Laycock-van Spyk 2011, Pros 2008). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes two nucleotides induces an early termination codon, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Laycock-van Spyk S et al. Neurofibromatosis type 1-associated tumours: their somatic mutational spectrum and pathogenesis. Hum Genomics. 2011 Oct;5(6):623-90. Pros E et al. Nature and mRNA effect of 282 different NF1 point mutations: focus on splicing alterations. Hum Mutat. 2008 Sep;29(9):E173-93.

Variant summary: NF1 c.983_984delGT (p.Cys328X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251436 control chromosomes (gnomAD). c.983_984delGT has been reported in the literature in individuals affected with Neurofibromatosis Type 1 (example: Abernathy_1997, Pros_2008, Thomas_2012, and Sabbagh_2013). These data indicate that the variant is likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 457880). This variant is also known as 982delGT. This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 9195229, 18546366, 22155606). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys328*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538).

The c.983_984delGT pathogenic mutation, located in coding exon 9 of the NF1 gene, results from a deletion of two nucleotides at nucleotide positions 983 to 984, causing a translational frameshift with a predicted alternate stop codon (p.C328*). This alteration has been seen in multiple individuals meeting clinical diagnosis criteria for Neurofibromatosis type 1 (Abernathy CR et al. Hum Mutat, 1997;9:548-54; Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Laycock-van Spyk S et al. Hum Genomics, 2011 Oct;5:623-90; Ambry Internal data). This alteration was observed with an allele frequency of 0.00014 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.0000 in 11,241 female controls of Japanese ancestry. In addition, it was observed with an allele frequency of 0.0000 in 53 unselected male breast cancer patients and was observed with an allele frequency of 0.0003 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). Of note, this alteration is also designated as 982delGT in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.