Submissions for variant NM_004333.6(BRAF):c.2128-5del

dbSNP: rs373442098

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037943	SCV000061608	likely benign	not specified	2012-07-13	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000037943	SCV000226780	benign	not specified	2015-05-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226379	SCV000288407	benign	RASopathy	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000284769	SCV000466956	likely benign	Cardio-facio-cutaneous syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000321054	SCV000466957	likely benign	Noonan syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000375627	SCV000466958	likely benign	Noonan syndrome with multiple lentigines	2016-06-14	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813337	SCV002060467	likely benign	Noonan syndrome and Noonan-related syndrome	2019-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037943	SCV003933751	benign	not specified	2023-05-10	criteria provided, single submitter	clinical testing	Variant summary: BRAF c.2128-5delT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.012 in 24396 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 2527.18 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRAF causing Cardiofaciocutaneous Syndrome phenotype (4.7e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2128-5delT in individuals affected with Cardiofaciocutaneous Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as benign (n = 2) or likely benign (n = 2). Based on the evidence outlined above, the variant was classified as benign.
Clinical Genetics, Academic Medical Center	RCV000037943	SCV001922881	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000037943	SCV001965804	benign	not specified		no assertion criteria provided	clinical testing