ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.1789C>G (p.Leu597Val) (rs121913369)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Database of Curated Mutations (DoCM) RCV000426915 SCV000504278 pathogenic Cutaneous melanoma 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437189 SCV000504279 likely pathogenic Neoplasm 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419516 SCV000504280 pathogenic Lung cancer 2014-10-02 no assertion criteria provided literature only
GeneDx RCV000505705 SCV000057238 pathogenic not provided 2017-05-15 criteria provided, single submitter clinical testing The L597V variant in the BRAF gene gene has been reported previously as a de novo variant in an individual with Noonan syndrome (Sarkozy et al., 2009). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L597V variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. Functional studies demonstrate that the L597V variant leads to increased protein activity (Sarkozy et al., 2009; Andreadi et al., 2012). Missense variants in nearby residues (F595L, G596V, T599R, V600G, K601Q, K601I, K601T) have been reported in the Human Gene Mutation Database in association with BRAF-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret L597V as a pathogenic variant.
GeneReviews RCV000208539 SCV000264344 pathogenic Noonan syndrome 1 2016-02-25 no assertion criteria provided literature only
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000015003 SCV000197134 pathogenic Non-small cell lung cancer 2016-04-21 no assertion criteria provided clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000033333 SCV000204067 pathogenic Noonan syndrome; Cardio-facio-cutaneous syndrome 2016-04-21 criteria provided, single submitter clinical testing The p.Leu597Val variant in BRAF has been previously reported in 4 individuals wi th clinical features of Noonan syndrome and Cardio-facio-cutaneous syndrome, inc luding one de novo occurrence (Sarkozy 2009, LMM data). It has not been identifi ed in large population studies. The p.Leu597Val has also been previously reporte d as a somatic mutation in melanomas and non-small cell lung carcinomas (NSCLC)( COSMIC). In vitro functional studies suggest that the p.Leu597Val variant may i mpact protein function (Wan 2004, Andreadi 2012, Sarkozy 2009). In summary, this variant meets the criteria to be classified as pathogenic for Noonan spectrum d isorders in an autosomal dominant manner based upon the de novo occurrence, stat istically significant increase of the allele frequency in affected individuals o ver the general population, and supporting functional evidence.
OMIM RCV000015003 SCV000035259 pathogenic Non-small cell lung cancer 2003-08-15 no assertion criteria provided literature only
OMIM RCV000030948 SCV000043972 pathogenic Noonan syndrome 7 2009-04-01 no assertion criteria provided literature only

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