Submissions for variant NM_001042492.3(NF1):c.2541T>C (p.Leu847=)

gnomAD frequency: 0.00010  dbSNP: rs147433258

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205310	SCV000259301	likely benign	Neurofibromatosis, type 1	2024-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000220939	SCV000272953	likely benign	Hereditary cancer-predisposing syndrome	2015-02-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781663	SCV000919878	benign	not specified	2018-02-26	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.2541T>C 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 observed variant frequency within African control individuals in the gnomAD database is approximately 3.41 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. To our knowledge, no occurrence of c.2541T>C in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Two 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 likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000205310	SCV001479202	likely benign	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001589089	SCV001822232	likely benign	not provided	2021-05-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000220939	SCV002527463	benign	Hereditary cancer-predisposing syndrome	2020-09-09	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000205310	SCV002560155	benign	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500641	SCV002809047	likely benign	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2022-04-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004553111	SCV004762423	likely benign	NF1-related disorder	2019-10-14	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).