Submissions for variant NM_004333.6(BRAF):c.1227A>G (p.Ser409=)

gnomAD frequency: 0.00318  dbSNP: rs145035762

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000033298	SCV000616391	benign	RASopathy	2017-04-03	reviewed by expert panel	curation	The filtering allele frequency of the c.1227A>G (p.Ser409=) variant in the BRAF gene is 0.313% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (233/66620 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Additionally, this variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). The p.Ser409= variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM, EGL Genetics internal data; GTR ID's: 21766, 26957, 500060; SCV000057203.8; SCV000061570.5; SCV000112807.7). Computational prediction tools and conservation analysis suggest that the p.Ser409= variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied: BA1, BP7, BP5, BP4.
GeneDx	RCV000680284	SCV000057203	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	RCV000037908	SCV000061570	benign	not specified	2012-01-30	criteria provided, single submitter	clinical testing	Ser409Ser in exon 10 of BRAF: This variant is not expected to have clinical sign ificance because it is not located within the splice consensus sequence, has bee n identified in 0.3% (20/7020) of European American chromosomes and <0.1% (2/373 8) of African American chromosomes by the NHLBI Exome sequencing project in a br oad population (http://evs.gs.washington.edu/EVS; dbSNP rs145035762)
Eurofins Ntd Llc (ga)	RCV000037908	SCV000112807	benign	not specified	2015-04-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000033298	SCV000252784	benign	RASopathy	2024-01-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000037908	SCV000310105	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000349078	SCV000466980	likely benign	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000290490	SCV000466982	likely benign	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000680284	SCV001473321	benign	not provided	2023-11-14	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813218	SCV002060460	benign	Noonan syndrome and Noonan-related syndrome	2020-04-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362605	SCV002664458	benign	Cardiovascular phenotype	2019-02-16	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	RCV000680284	SCV004161136	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	BRAF: BP4, BP7, BS1
Clinical Genetics, Academic Medical Center	RCV000037908	SCV001921003	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000680284	SCV001964905	likely benign	not provided		no assertion criteria provided	clinical testing