ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.1785T>G (p.Phe595Leu) (rs121913341)

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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 RCV000522002 SCV000616396 pathogenic Rasopathy 2017-04-03 reviewed by expert panel curation The c.1785T>G (p.Phe595Leu) variant in BRAF has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 19206169, 18042262; GTR ID's: 26957, 21766; ClinVar SCV000203922.4, SCV000207755.12). The variant has also been identified in at least 2 independent occurences in patients with clinical features of a RASopathy (PS4_Supporting; APHP-Robert Debré internal data; GTR ID 28338). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581, 16439621). 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). Computational prediction tools and conservation analysis suggest that the p.Phe595Leu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PM2, PM1, PP2, PP3, PS4_Supporting.
Database of Curated Mutations (DoCM) RCV000445270 SCV000505586 likely pathogenic Cutaneous melanoma 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426478 SCV000505587 likely pathogenic Neoplasm 2016-05-13 no assertion criteria provided literature only
GeneDx RCV000157825 SCV000207755 pathogenic not provided 2016-01-18 criteria provided, single submitter clinical testing The F595L missense variant in the BRAF gene has been reported previously in association with cardiofaciocutaneous syndrome, including instances of apparent de novo inheritance (Sarkozy et al., 2009; Rodriguez-Viciana et al., 2006), and its presence is consistent with the diagnosis in this patient. F595L 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. This substitution occurs at a position within 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 in nearby residues (G596V, L597V, T599R, V600G) have been reported in the Human Gene Mutation Database (HGMD) in association with Noonan-spectrum disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, two other variants in the same codon leading to the same T595L missense change, c.1783 T>C and c.1785 T>A, have also been reported in HGMD in association with Noonan-spectrum disorders.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154266 SCV000203922 likely pathogenic Cardio-facio-cutaneous syndrome 2014-04-01 criteria provided, single submitter clinical testing The Phe595Leu variant in BRAF has been reported in the literature in one individ ual with clinical features of Cardio-facio-cutaneous syndrome (CFC; Rodriguez-Vi ciana 2006). This same amino acid change caused by a different DNA change (c.178 5T>A) has also been reported to have occurred de novo in an individual with clin ical features of CFC syndrome (Schulz 2008). In addition, this variant was not i dentified in either parent of a proband (LMM unpublished data). Computational pr ediction tools and conservation analyses suggest that the Phe595Leu variant may impact the protein. In summary, this variant is likely pathogenic, though additi onal studies are required to fully establish its clinical significance.

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