Submissions for variant NM_001042492.3(NF1):c.3686A>G (p.Asn1229Ser)

gnomAD frequency: 0.00006  dbSNP: rs140523180

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164457	SCV000215100	benign	Hereditary cancer-predisposing syndrome	2015-12-06	criteria provided, single submitter	clinical testing	Co-occurence with mutation in same gene (phase unknown);Does not segregate with disease in family study (genes with complete penetrance);In silico models in agreement (benign)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473108	SCV000554904	likely benign	Neurofibromatosis, type 1	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000614422	SCV000729289	likely benign	not specified	2017-10-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Sema4, Sema4	RCV000164457	SCV002527529	likely benign	Hereditary cancer-predisposing syndrome	2021-02-23	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000473108	SCV002560685	likely benign	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000614422	SCV004030141	uncertain significance	not specified	2023-07-02	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.3686A>G (p.Asn1229Ser) results in a conservative amino acid change located in the Ras GTPase-activating domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251370 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3686A>G has been reported in the literature in individuals affected with Neurofibromatosis Type 1, however, authors reported the causative variant in this individual was NF1 c.1466A>G, p.Tyr489Cys (CV ID 354 Pathogenic), providing supporting evidence for a benign role (example: Ars_2003). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 12807981). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
PreventionGenetics, part of Exact Sciences	RCV004552890	SCV004721155	likely benign	NF1-related disorder	2020-01-09	no assertion criteria provided	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).