Submissions for variant NM_004333.6(BRAF):c.1914T>G (p.Asp638Glu)

dbSNP: rs180177042

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150199	SCV000197128	pathogenic	Cardio-facio-cutaneous syndrome	2013-08-27	criteria provided, single submitter	clinical testing	The Asp638Glu variant in BRAF has been reported to have occurred de novo in two individuals with clinical features of Cardio-facio-cutaneous syndrome (Sarkozy 2 009, Kleefstra 2011). Another variant at this nucleotide position resulting in the same amino acid residue change has also been reported in two individuals wit h clinical features of Cardio-facio-cutaneous syndrome including one de novo occ urrence (Sarkozy 2009, Rauen 2006). This variant was not identified in large po pulation studies. Studies have shown that the Asp638Glu variant impacts protein function (Rodriguez-Viciana 2008). In summary, the Asp638Glu variant meets our c riteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upo n its de novo occurrence in affected individuals, low allele frequency in the ge neral population, and supporting functional evidence.
GeneDx	RCV000157831	SCV000207761	pathogenic	not provided	2022-12-28	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic [(HGMD]; This variant is associated with the following publications: (PMID: 27171548, 30141192, 23093928, 25525159, 19206169, 18413255, 21063443, 30556322, 32369273, 33040082, 31069529, 34643321)
Ambry Genetics	RCV000624589	SCV000742118	pathogenic	Inborn genetic diseases	2017-01-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000689333	SCV000816979	pathogenic	RASopathy	2024-04-15	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 638 of the BRAF protein (p.Asp638Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (CFC) and Costello syndrome (PMID: 16804887, 18039235, 22495831). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 162797). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt BRAF function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRAF function (PMID: 18413255). For these reasons, this variant has been classified as Pathogenic.
Genomic Medicine Lab, University of California San Francisco	RCV000767527	SCV001167600	pathogenic	Cardiofaciocutaneous syndrome 1	2018-08-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000157831	SCV001247573	pathogenic	not provided	2020-11-01	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000150199	SCV005016614	pathogenic	Cardio-facio-cutaneous syndrome	2024-03-14	criteria provided, single submitter	clinical testing
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783752	SCV005397313	pathogenic	Noonan syndrome 7	2023-09-07	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (T>G) at position 1914 of the coding sequence of the BRAF gene that results in a aspartic acid to glutamic acid amino acid change at residue 638 of the B-Raf proto-oncogene, serine/threonine kise protein. The 638 residue falls in the kise domain (PMID: 18413255) which plays a critical role in BRAF function. This is a previously reported variant (ClinVar 162797) that has been observed in individuals affected by Costello syndrome (PMID: 16804887, 31069529) and cardiofaciocutaneous syndrome (PMID: 19206169, 37138575, 20859831, 21063443, 33040082, 27391121, 29095811, 22495831, 18039235, 37510243, 27940666, 31217210, 35524774, 34573299, 32369273), several of which were confirmed de novo (PMID: 19206169, 37138575, 20859831, 21063443). This variant is absent from the gnomAD population database (0/~250,000 alleles). Multiple bioinformatic tools predict that this Asp to Glu amino acid change would be damaging, and the Asp638 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant demonstrate impaired kise activity (PMID: 18413255). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PP2, PP3, PS1, PS3
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798786	SCV005420809	pathogenic	Melanoma	2024-10-04	criteria provided, single submitter	research	PM6,PS3,PM5,PM2,PP3
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000767527	SCV000898145	pathogenic	Cardiofaciocutaneous syndrome 1	2018-09-21	no assertion criteria provided	clinical testing
GenomeConnect - CFC International	RCV000999624	SCV001156331	not provided	Noonan syndrome 1		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 10-13-2014 by Lab or GTR ID 26957. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000157831	SCV001809483	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000157831	SCV001932077	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000157831	SCV001959358	pathogenic	not provided		no assertion criteria provided	clinical testing