ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.1801A>C (p.Lys601Gln) (rs121913364)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000034332 SCV000058307 pathogenic not provided 2013-03-18 criteria provided, single submitter clinical testing
GeneDx RCV000034332 SCV000329760 pathogenic not provided 2018-11-21 criteria provided, single submitter clinical testing The K601Q missense variant in the BRAF gene has been reported apparently de novo in two patients with cardio-facio-cutaneous syndrome and no family history of the disorder (Sarkozy et al., 2009). The K601Q 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. It is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in-silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies of the K601Q variant have demonstrated that it results in the enhances phosphorylation of MEK and ERK proteins (Sarkozy et al., 2009). In addition, missense variants at the same codon (K601I) and in nearby residues (G596V, L597V, T599R, V600G) 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 interpret K601Q to be a pathogenic variant.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000150201 SCV000197131 pathogenic Noonan syndrome; Cardio-facio-cutaneous syndrome 2019-01-02 criteria provided, single submitter clinical testing The p.Lys601Gln variant in BRAF has been identified as de novo occurrence in 3 i ndividuals with cardio-facio-cutaneous syndrome (Sarkozy 2009, LMM data). It was absent from large population studies. Computational prediction tools and in vit ro functional studies support an impact on protein function (Sarkozy 2009). The p.Lys601Gln variant has been observed as a somatic mutation in tumor specimens f rom colorectal cancer (Oliveira 2007) and melanoma (Long 2013). Furthermore, thi s variant is in the CR3 activation segment domain, which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF. Th is variant has also been reported in ClinVar (Variation ID #41446). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominan t cardio-facio-cutaneous syndrome. ACMG/AMP Criteria applied: PM6_Strong, PM1, P M2, PS4_Moderate, PS3_Supporting, PP3.

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