ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2970_2972del (p.Met992del) (rs267606606)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000196290 SCV000255279 pathogenic Neurofibromatosis, type 1 2018-12-02 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 22 of the NF1 mRNA (c.2970_2972delAAT). This leads to the deletion of 1 amino acid residue in the NF1 protein (p.Met991del) but otherwise preserves the integrity of the reading frame. While this variant is present in population databases (rs267606606, ExAC), the frequency information is unreliable due to low sequence quality at this site. This variant is reported to segregate with disease in several families with neurofibromatosis type 1 (NF1) (PMID: 17160901) and has been observed in many individuals with NF1-related conditions (PMID: 7904209, 12807981, 17160901, 20602485, 21532985, 23047742). Of note, cutaneous neurofibromas, a major feature of NF1, have not been observed so far in any individuals with this variant (PMID: 17160901). ClinVar contains an entry for this variant (Variation ID: 363). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. In summary, this variant is a rare in-frame deletion with uncertain impact on protein function. However, this variant has been reported to be a common recurrent mutation in patients with NF1-related conditions. For this reason, it has been classified as Pathogenic.
Ambry Genetics RCV000215737 SCV000273607 pathogenic Hereditary cancer-predisposing syndrome 2015-01-19 criteria provided, single submitter clinical testing
GeneDx RCV000384725 SCV000329840 pathogenic not provided 2018-11-26 criteria provided, single submitter clinical testing This in-frame deletion of 3 nucleotides in NF1 is denoted c.2970_2972delAAT at the cDNA level and p.Met992del (M992del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAAC[delAAT]GATG. This deletion of a single Methionine residue occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). This variant has been observed in many individuals with a clinical diagnosis or suspicion of neurofibromatosis type 1 (NF1), and was shown to segregate with disease in multiple large families (Shen 1993, Fahsold 2000, Messiaen 2000, Ars 2003, Castle 2003, De Luca 2005, Griffiths 2007, Upadhyaya 2007, Pros 2008, Muram-Zborovski 2010, Quintans 2011, Ben-Shachar 2013, van Minkelen 2014, Bianchessi 2015, Pasmant 2015, Cali 2016). Importantly, NF1 c.2970_2972delAAT has been suggested to be associated with a milder phenotype than classic NF1. Several reports in the literature suggest that individuals with this variant do not develop a major feature of NF1, cutaneous neurofibromas; rather, the reported phenotypic expression is mainly caf?-au-lait spots and skinfold freckling (Upadhyaya 2007). Only two publications to-date report individuals with NF1 c.2970_2972delAAT and cutaneous neurofibromas (De Luca 2005, Zhu 2016). Based on currently available evidence, we consider this variant to be pathogenic. Although multiple cutaneous neurofibromas are typically characteristic of NF1, absence in affected individuals in the literature suggests that NF1 c.2970_2972delAAT may be associated with a milder clinical presentation. Thus, the risks associated with classic NF1 pathogenic variants cited below might be overestimates and might not apply to this variant or others with an attenuated phenotype. A pathogenic variant in this gene is indicative of neurofibromatosis type 1 (NF1) syndrome, a highly penetrant autosomal dominant condition with a birth incidence of approximately 1 in 3000 individuals (Lammert 2005). NF1 is characterized by caf?-au-lait macules, freckling in the axillary or inguinal regions, multiple cutaneous neurofibromas, and iris Lisch nodules (iris hamartomas). Other manifestations include plexiform neurofibromas, learning disabilities, scoliosis, sphenoid dysplasia, tibial pseudarthrosis and vasculopathy. Brain tumors and optic nerve gliomas, the most common tumors in children with NF1 aside from neurofibromas, are typically benign and reported in approximately 2-3% and 15% of affected individuals, respectively (Ferner 2007). The most common malignant neoplasms associated with NF1 syndrome are malignant peripheral nerve sheath tumors (MPNST), which often develop in adolescence or early adulthood and occur in 6-13% of affected individuals (Evans 2002, McCaughan 2007). The prevalence of pheochromocytomas among individuals with NF1 syndrome is generally reported at 1-5% (Bosch 2006, Zelinka 2007, Toumpanakis 2008, Ferner 2013); however, higher rates have been reported at the time of autopsy (3-13%) (Walther 1999). Several studies have observed a higher than expected incidence of breast cancer in women with NF1 syndrome, particularly under the age of 50 years, and Easton et al. (2015) estimated the lifetime risk to be 26% (Walker 2006, Sharif 2007, Madanikia 2012, Wang 2012, Seminog 2015). While breast cancer in males with NF1 syndrome has been reported, the relative risk compared to the general population is not currently known (Wilson 2004, Seminog 2015). Other neoplasms that are over-represented in patients with NF1 syndrome include gastrointestinal stromal tumors (GISTs) (Miettinen 2006, Ferner 2013) and childhood leukemia (Stiller 1994, Yoshimi 2010). While the clinical features of NF1 syndrome are highly variable, even within the same family, most affected individuals meet diagnostic criteria in childhood. Approximately half of NF1 cases result from a de novo, rather than an inherited, pathogenic variant in the NF1 gene. The Neurofibromatosis 1 article in GeneReviews has management guidelines for individuals with pathogenic variants in NF1 (Friedman 2014).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000196290 SCV000711759 pathogenic Neurofibromatosis, type 1 2016-12-15 criteria provided, single submitter clinical testing The p.Met992del variant in NF1 has been previously reported in >20 individuals w ith NF1, segregated with disease in >20 affected relatives, and was de novo in a t least 1 of these individuals (Upadhyaya 2007, Quintans 2011). Individuals with this variant were reported to not have cutaneous neurofibromas (Upadhyaya 2007, Quintans 2011). This variant has also been reported in ClinVar (Variation ID: 3 63) and has been identified in 1/66338 European chromosomes by the Exome Aggrega tion Consortium (ExAC, This variant is a deleti on of 1 amino acid at position 992 and is not predicted to alter the protein rea ding frame. In summary, this variant meets our criteria to be classified as path ogenic for NF1 in an autosomal dominant manner based upon frequency in probands and segregation studies.
Center for Human Genetics, Inc RCV000196290 SCV000781967 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes RCV000384725 SCV000920468 pathogenic not provided 2018-01-16 criteria provided, single submitter clinical testing
OMIM RCV000000392 SCV000020536 pathogenic Neurofibromatosis-Noonan syndrome 2007-01-01 no assertion criteria provided literature only
OMIM RCV000000393 SCV000020537 pathogenic Café-au-lait macules with pulmonary stenosis 2007-01-01 no assertion criteria provided literature only

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