Submissions for variant NM_001042492.3(NF1):c.6855C>A (p.Tyr2285Ter)

dbSNP: rs772295894

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164442	SCV000215082	pathogenic	Hereditary cancer-predisposing syndrome	2015-05-21	criteria provided, single submitter	clinical testing	The p.Y2285*pathogenic mutation (also known as c.6855C>A) located in coding exon 46 of the NF1 gene, results from a C to A substitution at nucleotide position 6855. This changes the amino acid from a to a stop codon within coding exon 46.This is a recurrent mutation that has been detected in multiple patients and families with NF1 and has also been reported to result in-frame skipping of exon 37 (Robinson PN et al. Hum. Genet. 1995 Jul;96(1):95-8,Wimmer K et al. Hum. Mutat. 2007 Jun; 28(6):599-612,Sabbagh A et al. Hum. Mutat. 2013 Nov; 34(11):1510-8). In addition to the clinical information presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). This mutation is also known asp.Y2264* (c.6792C>A) in published literature.
Invitae	RCV000199249	SCV000253829	pathogenic	Neurofibromatosis, type 1	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr2264*) in the NF1 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with neurofibromatosis type 1 (PMID: 7607663, 9385374, 10607834, 12807981, 17311297, 26962827). ClinVar contains an entry for this variant (Variation ID: 185082). Studies have shown that this premature translational stop signal results in skipping of exon 45, but is expected to preserve the integrity of the reading-frame (PMID: 9385374, 10607834, 16870183, 22925204; Invitae). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000489640	SCV000576667	pathogenic	not provided	2021-10-26	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay, with some studies showing skipping of exon 37 in 20-30% of transcripts (Wimmer 2007, Hernandez-Imaz 2013); Observed de novo with and without confirmed parentage in multiple unrelated patients with neurofibromatosis type 1 referred for genetic testing at GeneDx and in published literature (Cali 2017); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31370276, 30530636, 28152038, 7607663, 27074763, 31730495, 32582540, 10494088, 17311297, 23913538, 25525159, 26962827, 27838393, 22925204, 30290804, 31766501, 31347283, 31645347, 31776437, 32623769, 33469372, 33911094, 34273915, 34080803, Kirat[article])
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000199249	SCV000782087	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000489640	SCV000842896	pathogenic	not provided	2017-11-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000489640	SCV000885840	pathogenic	not provided	2023-03-14	criteria provided, single submitter	clinical testing	The NF1 c.6855C>A; p.Tyr2285Ter variant (rs772295894), also known as c.6792C>A; p.Tyr2264Ter for NM_000267, is described as a recurrent variant associated with neurofibromatosis type 1 and studies have also shown it to cause exon skipping (Buske 1999, Hernandez-Imaz 2013, Robinson 1995, Sabbagh 2013, Wimmer 2007, Zhu 2016). This variant is also reported in ClinVar (Variation ID: 185082). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and 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: Buske A et al. Recurrent NF1 gene mutation in a patient with oligosymptomatic neurofibromatosis type 1 (NF1). Am J Med Genet. 1999 Oct 8;86(4):328-30. PMID: 10494088 Hernandez-Imaz E et al. Characterization of NF1 allele containing two nonsense mutations in exon 37 that segregates with neurofibromatosis type 1. Clin Genet. 2013 May;83(5):462-6. PMID: 22925204 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. PMID: 7607663 Sabbagh A et al. NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. Hum Mutat. 2013 Nov;34(11):1510-8. PMID: 23913538 Wimmer K et al. Extensive in silico analysis of NF1 splicing defects uncovers determinants for splicing outcome upon 5' splice-site disruption. Hum Mutat. 2007 Jun;28(6):599-612. PMID: 17311297 Zhu L et al. Clinical and Molecular Characterization of NF1 Patients: Single-Center Experience of 32 Patients From China. Medicine (Baltimore). 2016 Mar;95(10):e3043. PMID: 26962827
Fulgent Genetics, Fulgent Genetics	RCV000763393	SCV000894107	pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2018-10-31	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000199249	SCV001161704	pathogenic	Neurofibromatosis, type 1	2020-02-17	criteria provided, single submitter	clinical testing
Medical Genetics, University of Parma	RCV000199249	SCV001218928	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000199249	SCV001437221	pathogenic	Neurofibromatosis, type 1	2020-09-29	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.6792C>A (p.Tyr2264X) 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. In addition, multiple functional studies report experimental evidence that this variant affects mRNA splicing and results in exon 45 skipping (Hoffmeyer_1998, Ars_2000, Baralle_2006). The variant was absent in 251198 control chromosomes (gnomAD). c.6792C>A has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1 and cosegregated with the disease phenotype in families (Robinson_1995, Hoffmeyer_1998, Ars_2000, Assunto_2019). These data indicate that the variant is very likely to be associated with disease. Ten ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000199249	SCV001478906	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000489640	SCV001500119	pathogenic	not provided	2021-01-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000489640	SCV002018312	pathogenic	not provided	2021-09-07	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000199249	SCV002548795	pathogenic	Neurofibromatosis, type 1	2021-07-23	criteria provided, single submitter	clinical testing	The inherited heterozygous nonsense variant c.6855C>A, p.Tyr2285Ter identified in NF1 has been reported in individuals affected with NF1-related disorders (PMID:7607663, 9385374, 10607834, 12807981, 17311297, 26962827). The variant has one heterozygous in gnomAD v3.1.1 database indicating it is an extremely rare allele in the populations represented in this database. This variant is predicted to cause loss of normal protein function either through proteintruncation or nonsense-mediated mRNA decay. Loss of function variants in NF1 are known to be pathogenic. Based on the available evidence, the inherited c.6855C>A, p.Tyr2285Ter variant in the NF1 gene is classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000199249	SCV002558014	pathogenic	Neurofibromatosis, type 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurofibromatosis type 1 (NF1; MIM#162200). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. A child can be more severely affected than the carrier parent (PMID: 20301288). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent pathogenic variant associated with neurofibromatosis type 1 (ClinVar). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (external report). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genome-Nilou Lab	RCV000199249	SCV002560217	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000199249	SCV002579422	pathogenic	Neurofibromatosis, type 1	2021-08-09	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000199249	SCV002761861	pathogenic	Neurofibromatosis, type 1	2021-10-26	criteria provided, single submitter	clinical testing	The NF1 c.6855C>A variant is classified as Pathogenic (PVS1, PS4_Moderate, PS3, PM2, PP4) Also known as(NM_000267.3):c.6792C>G;p.(Tyr2264*) in exon 37
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000199249	SCV003926510	pathogenic	Neurofibromatosis, type 1	2023-05-25	criteria provided, single submitter	clinical testing
3billion	RCV000199249	SCV004013874	pathogenic	Neurofibromatosis, type 1		criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. This stop-gained (nonsense) variant is 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. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000185082/PMID:7607663/3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
PreventionGenetics, part of Exact Sciences	RCV004552888	SCV004106902	pathogenic	NF1-related disorder	2023-07-27	criteria provided, single submitter	clinical testing	The NF1 c.6855C>A variant is predicted to result in premature protein termination (p.Tyr2285*). This variant has also been referred to as c.6792C>A (p.Tyr2264*) in an alternate transcript (NM_000267.3). This variant has been identified in several unrelated individuals with neurofibromatosis type I and was found to be de novo in multiple cases (see for example, Robinson et al. 1995. PubMed ID: 7607663; Wimmer et al. 2007. PubMed ID: 17311297; Sabbagh et al. 2013. PubMed ID: 23913538; Zhu et al. 2016. PubMed ID: 26962827). This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185082/). Nonsense variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003467298	SCV004198343	pathogenic	Juvenile myelomonocytic leukemia	2023-08-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000489640	SCV004222179	pathogenic	not provided	2017-11-03	criteria provided, single submitter	clinical testing	The NF1 c.6792C>A (p.Tyr2264*, also known Y2264X) variant creates a premature stop codon in the NF1 gene. RNA studies have shown this variant does not trigger nonsense-mediated decay, but causes the in-frame skipping of exon 45 (also known as exon 37, c.2253_2286) in the NF1 gene (PMIDs: 22925204 (2013), 9463322 (1998), 9385374 (1997)). This variant has been reported in multiple individuals/families with neurofibromatosis type 1 (PMIDs: 30530636 (2019), 31347283 (2019), 31730495 (2019), 30290804 (2018), 26962827 (2016), 27322474 (2016), 23668869 (2013), 23913538 (2013), 17311297 (2007), 16479075 (2006), 15060124 (2004), 12807981 (2003), 12112660 (2002), 10607834 (2000)), including one de novo case (PMID: 27838393 (2017)). The frequency of this variant in the general population, 0.000007 (1/152150 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000489640	SCV004224738	pathogenic	not provided	2022-03-04	criteria provided, single submitter	clinical testing	PP1_strong, PM2, PS2, PS4_moderate, PVS1_moderate
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000199249	SCV005043923	pathogenic	Neurofibromatosis, type 1	2024-03-15	criteria provided, single submitter	clinical testing	PVS1, PS4, PS1, PM2, PM6
Molecular Oncology Initiative, University of California, San Francisco	RCV000851299	SCV000993589	pathogenic	Ewing sarcoma; Neurofibromatosis, type 1	2018-09-04	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162690	SCV002758185	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research