Submissions for variant NM_004333.6(BRAF):c.722C>A (p.Thr241Lys)

dbSNP: rs387906660

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000807047	SCV001424734	pathogenic	RASopathy	2020-06-25	reviewed by expert panel	curation	The c.722C>A (p.Thr241Lys) variant in BRAF was absent from large population studies (PM2; gnomad.broadinstitute.org). It has been identified in 1 individual with Noonan syndrome and 1 individual with cardiofaciocutaneous syndrome (PS4_Supporting; Otto von Guericke University Magdeburg internal data, Laboratory for Molecular Medicine internal data; ClinVar SCV000061619.5). It has been reported at least twice as a de novo occurrence without confirmation of maternity or paternity (PM6_Strong; Fulgent Genetics, Laboratory for Molecular Medicine internal data, SCV000061619.5). 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; 29493581). In addition, 3 other pathogenic or likely pathogenic variants have been identified at this codon (PM5 not applied; ClinVar ID: 29805, 29806, 29807). Computational prediction tools and conservation analysis suggest that the p.Thr241Lys variant in BRAF may impact the protein (PP3). This variant is located in BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PS4_Supporting, PM6_Strong, PM1, PM2, PP2, PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037953	SCV000061619	pathogenic	Noonan syndrome	2013-06-07	criteria provided, single submitter	clinical testing	The Thr241Lys variant has not been reported in the literature nor been identifie d in our laboratory in over 1,400 individuals. However, two nucleotide variants at this same position (722C>T, Thr241Met; 722C>G, Thr241Arg) have been previousl y reported in two patients with Noonan syndrome (Sarkozy 2009), one of which was shown to have occurred de novo. Moreover, an adjacent variant affecting the sam e amino acid codon (721A>C, Thr241Pro) has been identified in four patients with Cardio-facio-cutaneous syndrome or LEOPARD syndrome (Nava 2007, Schulz 2008, Sa rkozy 2009), with three of these patients having had the variant occur de novo. In addition, this variant was not identified in the parents of this proband. The se data suggest the threonine (Thr) at position 241, and residing within the con served region 1 (CR1) of BRAF, is a functionally important residue and is strong ly associated with Noonan Spectrum disorders. In summary, given the de novo occu rrence, the Thr241Lys variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
Invitae	RCV000807047	SCV000947075	likely pathogenic	RASopathy	2022-11-29	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Thr241 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17704260, 18042262, 19206169, 28404629). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 44829). This missense change has been observed in individual(s) with clinical features of RASopathy spectrum disorders (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 241 of the BRAF protein (p.Thr241Lys).