7-140801542-T-G

Position:

• chr7-140801542-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP2 PP3 PS2 PM6 PM2 PM1

This summary comes from the ClinGen Evidence Repository: The c.730A>C (p.Thr244Pro) variant in BRAF has been reported in the literature as a de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6 and PS2; PMID 17551924 and 18042262). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). This variant is in a location which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr244Pro 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): PP2, PP3, PM1, PM2, PM6, PS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA280025/MONDO:0015280/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 7.97

Genes affected

BRAF (HGNC:1097): (B-Raf proto-oncogene, serine/threonine kinase) This gene encodes a protein belonging to the RAF family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene, most commonly the V600E mutation, are the most frequently identified cancer-causing mutations in melanoma, and have been identified in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of lung. Mutations in this gene are also associated with cardiofaciocutaneous, Noonan, and Costello syndromes, which exhibit overlapping phenotypes. A pseudogene of this gene has been identified on the X chromosome. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1	c.730A>C	p.Thr244Pro	missense_variant	6/20	ENST00000644969.2
BRAF	NM_004333.6	c.730A>C	p.Thr244Pro	missense_variant	6/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.730A>C	p.Thr244Pro	missense_variant	6/20		NM_001374258.1
BRAF	ENST00000646891.2	c.730A>C	p.Thr244Pro	missense_variant	6/18		NM_004333.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Cardio-facio-cutaneous syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 20, 2023	Variant summary: BRAF c.730A>C (p.Thr244Pro) 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. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249582 control chromosomes (gnomAD). c.730A>C has been reported in the literature in multiple individuals affected with Cardiofaciocutaneous Syndrome, Noonan syndrome and related conditions (Gripp_2007, Schulz_2008, Rodriguez-Viciana_2008, van Trier_2016, Leach_2018), including one de novo case. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters, including ClinGen RASopathy Variant Curation Expert Panel, (evaluation after 2014) cite this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The c.730A>C (p.Thr244Pro) variant in BRAF has been reported in the literature as a de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6 and PS2; PMID 17551924 and 18042262). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). This variant is in a location which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr244Pro 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): PP2, PP3, PM1, PM2, PM6, PS2. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 19, 2014	The p.Thr244Pro variant in BRAF has been reported in the literature and our labo ratory in 6 individuals with RASopathies, three of which occurred de novo (Gripp 2007, Schulz 2008, LMM unpublished data). It was absent from large population s tudies. In summary, this variant meets our criteria to be classified as pathogen ic for RASopathies in an autosomal dominant manner (http://www.partners.org/pers onalizedmedicine/LMM) based upon de novo occurences and absence from controls. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 26150740, 18042262, 17551924, 24803665, 27521173, 30050098, 29907801, 24957944, 15488754, 16439621, 15520807, 17603483, 29493581) -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2019

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals with clinical features of the RASopathies spectrum. This variant occurred de novo in two of these affected individuals (PMID: 17551924, 27521173, 18042262). ClinVar contains an entry for this variant (Variation ID: 40346). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with proline at codon 244 of the BRAF protein (p.Thr244Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;.;D;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.7	.;.;L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.6	.;.;.;N
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0070	.;.;.;D
Sift4G	Benign	0.097	.;.;.;T
Polyphen		1.0	.;.;D;.
Vest4		0.88
MutPred		0.83		Loss of MoRF binding (P = 0.1019);Loss of MoRF binding (P = 0.1019);Loss of MoRF binding (P = 0.1019);Loss of MoRF binding (P = 0.1019);
MVP		0.98
MPC		2.1
ClinPred		0.96	D
GERP RS		4.0
Varity_R		0.84
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397507465; hg19: chr7-140501342;