Submissions for variant NM_004333.6(BRAF):c.722C>T (p.Thr241Met)

dbSNP: rs387906660

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000033281	SCV000057186	pathogenic	not provided	2022-04-06	criteria provided, single submitter	clinical testing	The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30414707, 19206169, 24803665, 28991257, 30525188, 32369273, 15488754, 16439621, 17603483, 24957944, 15520807, 29493581, 32368696, 33644862, 33040082, 33004838)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211753	SCV000061620	pathogenic	Noonan syndrome	2017-11-02	criteria provided, single submitter	clinical testing	The p.Thr241Met variant in BRAF has been previously reported in 3 individuals wi th clinical features of Noonan syndrome, including 2 de novo occurrences (LMM da ta, Sarkozy 2009, ClinVar Variation ID 29805). It has also been identified in 1/ 124756 European chromosomes by the Genome Aggregation Database (gnomAD, http://g nomad.broadinstitute.org; dbSNP rs387906660). Furthermore, 3 other missense vari ants at position p.241 (p.Thr241Arg, p.Thr241Pro, p.Thr241Lys) have been identif ied in individuals with clinical features of Noonan syndrome, Cardio-facio-cutan eous syndrome, LEOPARD, or Costello syndrome (Sarkozy 2009, LMM data), suggestin g that changes at this position are not tolerated. In summary, the p.Thr241Met v ariant meets criteria to be classified as pathogenic for Noonan syndrome in an a utosomal dominant manner. ACMG/AMP Criteria applied: PM5_Strong; PM6_Strong; PM2 ; PP2.
Fulgent Genetics, Fulgent Genetics	RCV000515432	SCV000611252	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	RCV000545320	SCV000659079	pathogenic	RASopathy	2022-04-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as 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, 23950000). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 29805). This missense change has been observed in individual(s) with Noonan Syndrome (PMID: 19206169). In at least one individual the variant was observed to be de novo. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 241 of the BRAF protein (p.Thr241Met).
SIB Swiss Institute of Bioinformatics	RCV000022678	SCV000803610	likely pathogenic	Noonan syndrome 7	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Likely Pathogenic, for Noonan syndrome 7, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:19206169). PM5 => Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Blueprint Genetics	RCV000033281	SCV000927841	pathogenic	not provided	2018-08-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001329218	SCV001520593	pathogenic	Cardiofaciocutaneous syndrome 1	2019-03-22	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in one patient with Noonan syndrome [PMID 19206169] Muscle weakness and peripheral neuropathy have been reported in individuals with CFC1 [PMID 16007634, 17437909, 22907230]
Institute of Human Genetics, University of Leipzig Medical Center	RCV000022678	SCV002044426	pathogenic	Noonan syndrome 7	2021-12-07	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2, PS4, PM5_STR, PM1, PM2_SUP, PP2, PP3
DASA	RCV000208540	SCV002061180	pathogenic	Noonan syndrome 1	2022-01-05	criteria provided, single submitter	clinical testing	The c.722C>T;p.(Thr241Met) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 29805; PMID: 19206169; 33040082; 30414707; 29522538; https://doi.org/10.1016/j.annonc.2021.08.1975) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (C1_1 domain) - PM1. This variant is not present in population databases (rs387906660, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (Clinvar ID: 29806; 29807; 44829) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 19206169; 30414707) - PM6. Missense variant in BRAF that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
New York Genome Center	RCV000022678	SCV002097853	pathogenic	Noonan syndrome 7	2021-01-29	criteria provided, single submitter	clinical testing	The heterozygousc.722C>T (p.Thr241Met) variant identified in the BRAF gene has been reported in multiple individuals affected with Noonan, LEOPARD, and Cardio-facio-cutaneous syndromes (PMID: 19206169,32369273). The p.Thr241Met variant has also been reported in anindividual affected with moderate intellectual disability and generalized epilepsy (PMID:30525188). This variant has been reported as heterozygous in one out of 152,100 individuals in the gnomAD(v3) database suggesting it is extremely rare in the populations represented in gnomAD. The variant affects an evolutionary conserved residue and is predicted deleterious by multiple in silico prediction tools. The variant is reported in the ClinVar database as pathogenic/likely pathogenic by multiple independent laboratories (ClinVarID: 29805). A different missense variant affecting the same residue Thr241 has also been reported in individuals affected with Cardio-facio-cutaneous syndrome suggesting that p.Thr241is important for the normalprotein function. Based on the available evidence, the heterozygousc.722C>T (p.Thr241Met) variant identified in the BRAF gene is reported here as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230371	SCV003929360	pathogenic	Cardio-facio-cutaneous syndrome	2023-04-24	criteria provided, single submitter	clinical testing	Variant summary: BRAF c.722C>T (p.Thr241Met) results in a non-conservative amino acid change located in the Protein kinase C-like, phorbol ester/diacylglycerol-binding domain (IPR002219) 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 (gnomAD). c.722C>T has been reported in the literature in multiple individuals affected with Cardiofaciocutaneous Syndrome, Noonan Syndrome and Congenital heart disease (examples: Sarkozy_2009, Jin_2017, Okuzono_2019, Edwards_2020, Lee_2021, and Hiraide_2021) and multiple cases are reported as de novo occurrences (examples: Jin_2017, Okuzono_2019, Edwards_2020, and Hiraide_2021). These data indicate that the variant is very likely to be associated with disease. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000033281	SCV004010732	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	BRAF: PS2, PM5, PM2:Supporting, PP2, PP3, PS4:Supporting
PreventionGenetics, part of Exact Sciences	RCV003398558	SCV004102979	pathogenic	BRAF-related condition	2023-09-15	criteria provided, single submitter	clinical testing	The BRAF c.722C>T variant is predicted to result in the amino acid substitution p.Thr241Met. This variant was reported in numerous individuals with BRAF-associated disorders, including at least four de novo cases (Okuzono et al. 2019. PubMed ID: 30414707; supplementary database 2, Edwards et al. 2020. PubMed ID: 32368696; Table S1, Kosaki et al. 2020. PubMed ID: 32369273; Hiraide et al. 2021. PubMed ID: 33644862; Swarts et al. 2022. PubMed ID: 35979676). This variant is reported in 0.00079% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-140501350-G-A). This variant is interpreted as pathogenic.
OMIM	RCV000022678	SCV000043967	pathogenic	Noonan syndrome 7	2009-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000208540	SCV000264341	not provided	Noonan syndrome 1		no assertion provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000033281	SCV001808076	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000033281	SCV001952678	pathogenic	not provided		no assertion criteria provided	clinical testing
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000208540	SCV003840168	pathogenic	Noonan syndrome 1		no assertion criteria provided	research