ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.1403T>C (p.Phe468Ser) (rs397507473)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033305 SCV000057210 pathogenic not provided 2016-12-07 criteria provided, single submitter clinical testing The F468S variant has been published previously in association with disorders in the RASopathy spectrum, including patients in which the variant was confirmed as de novo (Gripp et al., 2007; Schulz et al., 2008; Rodriguez-Viciana et al., 2006). It is reported as pathogenic in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000061579.4; Landrum et al., 2015). The variant 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. F468S 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 Glycine-rich loop of the protein kinase domain that is conserved across species. Missense variants in nearby residues (G464V/R, S467A, G469R/E, 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. Therefore, we consider this variant to be pathogenic
Invitae RCV000797502 SCV000937062 pathogenic Rasopathy 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 468 of the BRAF protein (p.Phe468Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is present in population databases (rs397507473, ExAC 0.001%). This variant has been observed to be de novo and otherwise in individuals with cardio-facio-cutaneous syndrome and RASopathy disorders (PMID: 18042262, 17551924, 29084544, 16439621). ClinVar contains an entry for this variant (Variation ID: 40366). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037917 SCV000061579 pathogenic Cardio-facio-cutaneous syndrome 2009-06-02 criteria provided, single submitter clinical testing

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