Submissions for variant NM_001042492.3(NF1):c.6852_6855del (p.Tyr2285fs)

dbSNP: rs1555535032

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000196480	SCV000255282	pathogenic	Neurofibromatosis, type 1	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr2264Thrfs*5) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 and with neurofibromatosis-Noonan syndrome (PMID: 7607663, 16835897, 24357598, 25325900). This variant is also known as c.6850_6853delACTT. ClinVar contains an entry for this variant (Variation ID: 216866). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Department of Research and Development, Institute Hermes Pardini	RCV000196480	SCV000264655	pathogenic	Neurofibromatosis, type 1	2016-02-02	criteria provided, single submitter	research	PVS1 - disrupt gene (frameshift), PM2 - Absent in population databases, PM4 - Protein lenght change, PP3 - Multiple deleterious effect and PP4 - Patient's phenotype
Ambry Genetics	RCV000492169	SCV000581263	pathogenic	Hereditary cancer-predisposing syndrome	2016-02-06	criteria provided, single submitter	clinical testing	Thec.6852_6855delTTACpathogenic mutation (also known as c.6789_6792delTTACand6789del-TTAC), located in codingexon46 of theNF1gene, results from a deletion of 4 nucleotides from positions 6852 to6855, causing a translationalframeshiftwith a predicted alternate stopcodon(p.Y2285Tfs*5). This pathogenic mutation has beenreported in severalindividuals whofulfilledNIH diagnostic criteria for NF1 (Robinson PN et al.HumGenet.1995;96(1):95-8, Griffiths S, et al.Fam. Cancer 2007 ; 6(1):21-34).In addition to the clinical data presented in the literature, sinceframeshiftsare typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMGRecommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007.Genet Med.2008;10:294).
GeneDx	RCV000520162	SCV000617589	pathogenic	not provided	2022-02-03	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24357598, 30530636, 31371350, 16835897, 7607663, 16944272, 19738042, 27980226, 25325900, 31776437, 34427956)
Athena Diagnostics	RCV000520162	SCV000842895	pathogenic	not provided	2022-07-22	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features of NF1, including at least one apparent de novo.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002584	SCV001160557	pathogenic	not specified	2019-05-03	criteria provided, single submitter	clinical testing	The NF1 c.6852_6855delTTAC; p.Tyr2285fs variant (rs863224836), also known as c.6789_6792delTTAC for NM_000267.3, is reported in the literature in multiple individuals and families affected with neurofibromatosis type 1 (Banerjee 2017, Brems 2009, Griffiths 2007, Lee 2006, Robinson 1995), and a family affected with neurofibromatosis-Noonan syndrome (Ekvall 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 216866), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 4 nucleotides, 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: Banerjee S et al. Novel phenotypes of NF1 patients from unrelated Chinese families with tibial pseudarthrosis and anemia. Oncotarget. 2017 Jun 13;8(24):39695-39702. Brems H et al. Glomus tumors in neurofibromatosis type 1: genetic, functional, and clinical evidence of a novel association. Cancer Res. 2009 Sep 15;69(18):7393-401. Ekvall S et al. Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome. Am J Med Genet A. 2014 Mar;164A(3):579-87. Griffiths S et al. Molecular diagnosis of neurofibromatosis type 1: 2 years experience. Fam Cancer. 2007;6(1):21-34. Lee MJ et al. Identification of forty-five novel and twenty-three known NF1 mutations in Chinese patients with neurofibromatosis type 1. Hum Mutat. 2006 Aug;27(8):832. Robinson PN et al. Two recurrent nonsense mutations and a 4 bp deletion in a quasi-symmetric element in exon 37 of the NF1 gene. Hum Genet. 1995 Jul;96(1):95-8.
Medical Genetics, University of Parma	RCV000196480	SCV001218927	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000196480	SCV001479112	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
3billion	RCV001775098	SCV002012262	pathogenic	Neurofibromatosis-Noonan syndrome	2021-10-02	criteria provided, single submitter	clinical testing	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab	RCV000196480	SCV002560214	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000196480	SCV004023355	pathogenic	Neurofibromatosis, type 1	2023-08-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468912	SCV004198279	pathogenic	Juvenile myelomonocytic leukemia	2024-01-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000520162	SCV004222178	pathogenic	not provided	2022-07-22	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the NF1 mRNA and causes the premature termination of NF1 protein synthesis. In addition, this variant has been reported in individuals affected with neurofibromatosis and in a family with neurofibromatosis-Noonan syndrome in the published literature (PMIDs: 19738042 (2009), 7607663 (1995), 16835897 (2006), 25325900 (2014), 27980226 (2017) and 24357598 (2014)). Based on the available information, this variant is classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000196480	SCV005061237	pathogenic	Neurofibromatosis, type 1		criteria provided, single submitter	clinical testing	The observed frameshift variant c.6852_6855del (p.Tyr2285ThrfsTer5) in NF1 gene has been reported previously in multiple individuals affected with Neurofibromatosis Type 1 (Maruoka et al. 2014; Riva et al. 2022). The p.Tyr2285ThrfsTer5 variant is absent in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Tyrosine 2285, changes this amino acid to Threonine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Tyr2285ThrfsTer5. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in NF1 gene have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Genome Sciences Centre, British Columbia Cancer Agency	RCV000786037	SCV000924578	likely pathogenic	Ganglioglioma	2019-05-21	no assertion criteria provided	research
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000196480	SCV001190742	pathogenic	Neurofibromatosis, type 1	2020-02-05	no assertion criteria provided	clinical testing