Submissions for variant NM_004333.6(BRAF):c.740T>C (p.Phe247Ser)

dbSNP: rs397507467

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000788011	SCV000927043	likely pathogenic	Noonan syndrome and Noonan-related syndrome	2019-05-10	reviewed by expert panel	curation	The c.740T>C (p.Phe247Ser) 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, PS4_Supporting; GeneDx internal data; GTR Lab ID: 26957; NOT SUBMITTED TO CLINVAR YET). A different pathogenic missense variant has been previously identified at this codon of BRAF which may indicate that this residue is critical to the function of the protein (PM5 not applied due to PM1 application; ClinVar 55793, 180784). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.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). 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.Phe247Ser variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PS4_Supporting, PM2, PM1, PP2, PP3.
GeneDx	RCV001703443	SCV000057191	pathogenic	not provided	2023-07-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as likely pathogenic by the ClinGen RASopathy Expert Panel (VCV000040349.1, ClinVar; Gelb et al., 2018); This variant is associated with the following publications: (PMID: 28580939, 27478437, 24957944, 15488754, 16439621, 15520807, 17603483, 29493581)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003539763	SCV004343175	likely pathogenic	RASopathy	2023-07-26	criteria provided, single submitter	clinical testing	This variant disrupts the p.Phe247 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2851224; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 247 of the BRAF protein (p.Phe247Ser). ClinVar contains an entry for this variant (Variation ID: 40349). This missense change has been observed in individual(s) with clinical features of BRAF-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency).