Submissions for variant NM_004333.6(BRAF):c.64G>A (p.Asp22Asn)

gnomAD frequency: 0.00025  dbSNP: rs397507456

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000520051	SCV000616392	benign	RASopathy	2017-04-03	reviewed by expert panel	curation	The variant c.64G>A (p.Asp22Asn) in BRAF was observed in a healthy adult individual who did not have clinical features of a RASopathy (BS2; Partners LMM and GeneDx internal data; GTR ID's: 21766, 26957; SCV000061615.5, SCV000057172.10). This variant has been observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder (BP2_Strong; LabCorp internal data GTR ID: 500026, ClinVar SCV000698345.1). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP2_S, BS2.
GeneDx	RCV000590699	SCV000057172	benign	not provided	2016-05-31	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037950	SCV000061615	uncertain significance	not specified	2015-02-19	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590699	SCV000698345	benign	not provided	2017-07-17	criteria provided, single submitter	clinical testing	Variant summary: The BRAF c.64G>A (p.Asp22Asn) variant involves the alteration of a conserved nucleotide and 2/4 in silico tools (SNPsandGO not captured due to low reliability index)predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 106/151790 control chromosomes, predominantly observed in East Asian subpopulation at a frequency of 0.009248 (102/11030). This frequency is about 3699 times the estimated maximal expected allele frequency of a pathogenic BRAF variant (0.0000025), suggesting this is likely a benign polymorphism found primarily in population(s) of East Asian origin. Multiple publications have cited the variant in individuals affected with various cancers indicated predominantly being a somatic occurrence, although limited information as to whether the variant was eliminated from being a germline occurrence was indicated. An internal LCA sample carrying this variant also carried another pathogenic variant PTPN11 p.Thr42Ala. Multiple clinical diagnostic laboratories have conflicting classifications "benign" or "uncertain significance." However, due the high occurrence in controls and the co-occurrence with a pathogenic PTPN11 variant, the variant of interest has been classified as Benign.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000853030	SCV000995787	benign	Cardiomyopathy	2019-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001160946	SCV001322785	uncertain significance	LEOPARD syndrome 3	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001160947	SCV001322786	uncertain significance	Noonan syndrome 7	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000520051	SCV001716800	benign	RASopathy	2024-01-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590699	SCV002049575	benign	not provided	2021-05-12	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813216	SCV002060474	benign	Noonan syndrome and Noonan-related syndrome	2021-01-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354178	SCV002655547	benign	Cardiovascular phenotype	2022-03-14	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
CeGaT Center for Human Genetics Tuebingen	RCV000590699	SCV004042323	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	BRAF: BS1
Breakthrough Genomics, Breakthrough Genomics	RCV000590699	SCV005270707	benign	not provided		criteria provided, single submitter	not provided
ITMI	RCV000037950	SCV000084406	not provided	not specified	2013-09-19	no assertion provided	reference population
PreventionGenetics, part of Exact Sciences	RCV003904885	SCV004722550	benign	BRAF-related disorder	2019-08-09	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).