Submissions for variant NM_001042492.3(NF1):c.2553C>T (p.Cys851=)

gnomAD frequency: 0.00190  dbSNP: rs2230852

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130541	SCV000185410	benign	Hereditary cancer-predisposing syndrome	2014-12-01	criteria provided, single submitter	clinical testing	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084162	SCV000252679	benign	Neurofibromatosis, type 1	2025-02-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000217841	SCV000269451	benign	not specified	2014-11-24	criteria provided, single submitter	clinical testing	Cys851Cys in exon 21 of NF1: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 0.7% (33/4406) of Afr ican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2230852).
GeneDx	RCV000680357	SCV000529105	likely benign	not provided	2021-02-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000217841	SCV000595971	likely benign	not specified	2016-07-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000217841	SCV000919884	benign	not specified	2018-08-13	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.2553C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00053 in 276370 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0054 in the gnomAD database, including 1 homozygote. The observed variant frequency within African control individuals in the gnomAD database is approximately 26 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 phenotype (0.00021), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. However, the region is highly homologous to pseudogenes, and the technology utilized for this dataset does not rule out pseudogene interference making ExAC and gnomAD data unreliable for assessing variant frequency. To our knowledge, no occurrence of c.2553C>T in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as Benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001084162	SCV001478988	benign	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130541	SCV002527464	benign	Hereditary cancer-predisposing syndrome	2020-09-19	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV001084162	SCV002560211	benign	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130541	SCV004228009	benign	Hereditary cancer-predisposing syndrome	2023-11-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000680357	SCV005436041	likely benign	not provided	2024-10-01	criteria provided, single submitter	clinical testing	NF1: BP4, BP7