ClinVar Miner

Submissions for variant NM_001374258.1(BRAF):c.1526G>A (p.Gly509Glu) (rs121913355)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000211748 SCV000616361 pathogenic Cardio-facio-cutaneous syndrome 2017-04-03 reviewed by expert panel curation The c.1406G>A (p.Gly469Glu) variant in BRAF has been reported in the literature as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 18042262, 16474404). In vitro functional studies provide some evidence that the p.Gly469Glu variant may impact protein function (PS3; 16474404). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Furthermore, this variant is in a location which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Gly469Glu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PS2_VeryStrong, PS3.
GeneDx RCV000212152 SCV000057212 pathogenic not provided 2017-01-10 criteria provided, single submitter clinical testing The G469E pathogenic variant in the BRAF gene has been reported previously in association with Cardio-Facio-Cutaneous (CFC) syndrome, including de novo occurrences (Niihori et al., 2006; Schulz et al., 2008; Sarkozy et al., 2009). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. G469E is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the ATP nucelotide binding region of the protein kinase domain that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same (G469R) and in nearby residues (G464R/V, S467A, F468S, T470P) have been reported in the Human Gene Mutation Database in association with cardio-facio-cutaneous syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, functional studies of the G469E variant have shown that it results in reduced B-Raf protein activity and decreased induction of MEK and ERK phosphorylation (Rodriguez-Viciana et al., 2006; Niihori et al., 2006). Therefore, we interpret the G469E variant as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211748 SCV000061581 pathogenic Cardio-facio-cutaneous syndrome 2011-07-26 criteria provided, single submitter clinical testing The Gly469Glu variant has been reported in the literature in several individuals with clinical features of Cardio-facio-cutaneous syndrome (Niihori 2006, Schulz 2008). In addition, this variant was reported to have occurred de novo in three of those individuals. Therefore, this variant is highly likely to be pathogenic .
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000212152 SCV000225337 pathogenic not provided 2014-07-27 criteria provided, single submitter clinical testing
Invitae RCV000033307 SCV000553832 pathogenic Rasopathy 2019-08-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 469 of the BRAF protein (p.Gly469Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases at a very low frequency (rs121913355, ExAC <0.01%). This variant has been reported in the literature in individuals affected with cardiofaciocutaneous syndrome (PMID: 16474404, 19206169, 18042262, 16439621). In at least one individual this change was reported to be a de novo event and was not present in the proband's unaffected parents (PMID: 18042262). ClinVar contains an entry for this variant (Variation ID: 13974) Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change that is predicted to disrupt protein function and has been reported in multiple affected individuals. For these reasons, it has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506575 SCV000602657 pathogenic not specified 2017-03-10 criteria provided, single submitter clinical testing
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000015008 SCV000999285 pathogenic Cardiofaciocutaneous syndrome 1 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000211748 SCV001363181 pathogenic Cardio-facio-cutaneous syndrome 2019-12-09 criteria provided, single submitter clinical testing Variant summary: BRAF c.1406G>A (p.Gly469Glu) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251520 control chromosomes. c.1406G>A has been reported in the literature as a de-novo variant in multiple individuals affected with Cardiofaciocutaneous Syndrome (example, Nihori_2006, Smalley_2009, Sarkozy_2009, Pandit_2007, Schultz_2008, Greaves_2013, Ciara_2015, Lee_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an induction of ERK activation by trigerring C-RAF activity as a distinct mechanism of action (Wan_2004). Five clinical diagnostic laboratories and one expert panel (ClinGen RASopathy panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000015008 SCV000035264 pathogenic Cardiofaciocutaneous syndrome 1 2006-03-01 no assertion criteria provided literature only
Baylor Genetics RCV000033307 SCV000196670 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
Database of Curated Mutations (DoCM) RCV000424773 SCV000504335 pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434590 SCV000504336 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443381 SCV000504337 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427215 SCV000504338 likely pathogenic Cutaneous melanoma 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437869 SCV000504339 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419576 SCV000504340 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427006 SCV000504341 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436804 SCV000504342 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419555 SCV000504343 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000015008 SCV000747832 pathogenic Cardiofaciocutaneous syndrome 1 2017-12-25 no assertion criteria provided clinical testing The observed variant c.1406G>A (p.G469E) is not reported in 1000 Genomes and has a minor allele frequency of 0.000008238 in ExAC databases. The in silico prediction of the variant is disease causing by MutationTaster2, damaging by SIFT, and probably damaging by PolyPhen2.
GenomeConnect - CFC International RCV000211748 SCV001156333 not provided Cardio-facio-cutaneous syndrome no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 12-02-2009 by Lab or GTR ID 21766. 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.

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