ClinVar Miner

Submissions for variant NM_001374258.1(BRAF):c.1553-19A>G (rs369635503)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000522961 SCV000616394 benign Rasopathy 2017-04-03 reviewed by expert panel curation The c.1433-19A>G variant in BRAF has been identified in at least 2 patients with clinical features of a RASopathy (PS4_Supporting; GeneDx, Greenwood Genetics, Otto von Guericke University Magdeburg, internal data, GTR ID's: 26957, 1019; ClinVar SCV000207632.1, SCV000167210.14). However, the filtering allele frequency of the c.1433-19A>G variant in the BRAF gene is 0.11% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (120/65832 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). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data, GTR ID's: 26957; ClinVar SCV000167210.14). This variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, BA1, BP5, BP7.
GeneDx RCV000123867 SCV000167210 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.
PreventionGenetics,PreventionGenetics RCV000157706 SCV000310107 likely benign not specified criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000157706 SCV001338968 benign not specified 2020-03-23 criteria provided, single submitter clinical testing Variant summary: BRAF c.1433-19A>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00098 in 251054 control chromosomes, predominantly at a frequency of 0.002 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is significantly higher than the estimated maximal expected allele frequency for a pathogenic variant in BRAF causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1433-19A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, two classified as likely benign/benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as benign.
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000123867 SCV000207632 uncertain significance not provided 2015-01-15 no assertion criteria provided clinical testing

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