Submissions for variant NM_004333.6(BRAF):c.721A>C (p.Thr241Pro)

dbSNP: rs387906661

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211752	SCV000061618	pathogenic	Cardio-facio-cutaneous syndrome	2012-06-26	criteria provided, single submitter	clinical testing	The Thr241Pro variant in BRAF has been reported in the literature in four indivi duals with clinical features of Cardio-facio-cutaneous syndrome, LEOPARD, or Cos tello syndrome (Nava 2007, Schulz 2008, Sarkozy 2009). This variant was reported to have occurred de novo in three of those individuals. Therefore, this variant meets our criteria to be classified as pathogenic.
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000207516	SCV000263060	likely pathogenic	not provided	2015-07-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515363	SCV000611251	pathogenic	Cardiofaciocutaneous syndrome 1; Lung carcinoma; Noonan syndrome 1; LEOPARD syndrome 3; Noonan syndrome 7	2017-05-18	criteria provided, single submitter	clinical testing
Invitae	RCV000654966	SCV000776876	pathogenic	RASopathy	2021-04-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.The241Met amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19206169). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BRAF protein function (PMID: 28404629). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRAF protein function. This variant has been observed in individual(s) with cardio–facio–cutaneous syndrome (PMID: 17704260, 18042262). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 29807). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with proline at codon 241 of the BRAF protein (p.Thr241Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline.
Blueprint Genetics	RCV000207516	SCV000927223	pathogenic	not provided	2017-04-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211752	SCV002500556	pathogenic	Cardio-facio-cutaneous syndrome	2022-03-21	criteria provided, single submitter	clinical testing	Variant summary: BRAF c.721A>C (p.Thr241Pro) results in a non-conservative amino acid change located in the Cysteine-rich (CRD) domain (Sarkozy_2009) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248524 control chromosomes. c.721A>C has been reported in the literature as a sporadic/de-novo variant in individuals affected with Cardiofaciocutaneous Syndrome/Leopard Syndrome (example, Nava_2007, Schulz_2008, Sarkozy_2009, Sekiguchi_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a moderate level of activation as measured by NIH-3T3 colony focus formation and a moderate increase in MEK and ERK phosphorylation in-vitro (example, Sarkozy_2009). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
MGZ Medical Genetics Center	RCV002288517	SCV002579800	pathogenic	Noonan syndrome 7	2022-01-11	criteria provided, single submitter	clinical testing
OMIM	RCV000022680	SCV000043969	pathogenic	Cardiofaciocutaneous syndrome 1	2009-04-01	no assertion criteria provided	literature only
OMIM	RCV000022681	SCV000043970	pathogenic	LEOPARD syndrome 3	2009-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000055896	SCV000086904	not provided	Noonan syndrome with multiple lentigines		no assertion provided	literature only
GenomeConnect - CFC International	RCV001089761	SCV001245255	not provided	Cardiofaciocutaneous syndrome 1; LEOPARD syndrome 3; Noonan syndrome 7		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 08-30-2016 by Lab or GTR ID 500105. 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.