ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.739T>C (p.Phe247Leu)

dbSNP: rs397516903
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000788010 SCV000927042 pathogenic Noonan syndrome and Noonan-related syndrome 2019-05-10 reviewed by expert panel curation The c.739T>C (p.Phe247Leu) variant in BRAF has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; GeneDx internal data; GTR Lab ID: 26957; ClinVar SCV000207748.12). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Phe247Leu variant may impact protein function (PS3; PMID: 28512244). The c.739T>C variant results in the same amino acid change as the previously established pathogenic c.741T>G (p.Phe247Leu) variant (PS1; ClinVar ID 55793). 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). 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.Phe247Leu 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): PM6, PM2, PS3, PS1, PM1, PP2, PP3.
GeneDx RCV000157818 SCV000207748 pathogenic not provided 2022-01-14 criteria provided, single submitter clinical testing Published functional studies demonstrate MAPK activation (Lu et al., 2017); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 16474404, 26243863, 28512244, 28676128, 33128510, 33040082, 24957944, 15488754, 16439621, 15520807, 17603483, 29493581)
Invitae RCV000809145 SCV000949286 pathogenic RASopathy 2023-08-14 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRAF function (PMID: 2851224). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt BRAF function. ClinVar contains an entry for this variant (Variation ID: 180784). This missense change has been observed in individual(s) with clinical features of BRAF-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 247 of the BRAF protein (p.Phe247Leu).
3billion RCV001808428 SCV002058744 pathogenic Noonan syndrome 7 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000055793,VCV000180784, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 28512244, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.902, PP3_P). A missense variant is a common mechanism associated with Noonan syndrome 7 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040349, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Service de Génétique Moléculaire, Hôpital Robert Debré RCV000824913 SCV000965944 likely pathogenic Noonan syndrome no assertion criteria provided clinical testing
GenomeConnect - CFC International RCV001803101 SCV002047675 not provided Cardiofaciocutaneous syndrome 1; Noonan syndrome 1 no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 12-03-2018 by lab or GTR ID GeneDx. 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. Phenotypic details are available under supporting information.

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