rs794729219

Positions:

• chr7-140753352-A-G
• chr7-140753352-A-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001374258.1(BRAF):​c.1903T>C​(p.Phe635Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 9.24

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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BRAF. . Gene score misZ 3.7208 (greater than the threshold 3.09). Trascript score misZ 4.9008 (greater than threshold 3.09). GenCC has associacion of gene with LEOPARD syndrome 3, anaplastic astrocytoma, Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome 7.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 7-140753352-A-G is Pathogenic according to our data. Variant chr7-140753352-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 202193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1903T>C	p.Phe635Leu	missense_variant	16/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1783T>C	p.Phe595Leu	missense_variant	15/18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1903T>C	p.Phe635Leu	missense_variant	16/20		NM_001374258.1	ENSP00000496776
BRAF	ENST00000646891.2	c.1783T>C	p.Phe595Leu	missense_variant	15/18		NM_004333.6	ENSP00000493543	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiofaciocutaneous syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Mendelics	Nov 06, 2013	- -

Cardio-facio-cutaneous syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 31, 2022

Variant summary: BRAF c.1783T>C (p.Phe595Leu) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) 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 251240 control chromosomes (gnomAD). c.1783T>C has been reported in the literature in individuals affected with Cardiofaciocutaneous Syndrome (Ciara_2015, Matalon_2021), and in one case the de novo occurrence of the variant was confirmed. In addition two equivalent missense variants (c.1785T>A (p.F595L) and c.1785T>G (p.F595L)) have also been reported in patients affected with Cardio-facio-cutaneous syndrome (HGMD). These data indicate that the variant is likely associated with disease. Multiple publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant results in low to intermediate Braf kinase activity, which works cooperatively with Ras leading to increased MEK/ERK signaling (Kordes_2016, Yao_2017, Ng_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant in the germline state to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 11, 2023

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; Also known as p.(F594L); This variant is associated with the following publications: (PMID: 22142829, 24803665, 37039257, 33683002, 28856074, 34573299, 31060855, 32913992, 18039235, MelchorL2015[Abstract], 31573083, 33128510, 29533785, 19206169, 20186801, 18042262, 21871821, 22495831, 29084544, 23093928, 35226061, 33198372, 34331515, 36448195, 26826419, 37530550, 26582644, 16439621, 15035987, 25463315, 24957944, 15488754, 15520807, 17603483, 29493581) -

Melanoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2023

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 595 of the BRAF protein (p.Phe595Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardio-facio-cutaneous (CFC) syndrome (PMID: 16439621, 18042262, 19206169, 20186801, 21871821, 22495831, 23093928, 25463315, 29084544). In at least one individual the variant was observed to be de novo. This variant is also known as F594L. ClinVar contains an entry for this variant (Variation ID: 202193). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRAF function (PMID: 26582644). For these reasons, this variant has been classified as Pathogenic. -

Prostate cancer, hereditary, 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Laboratory of Virology, Oncology, Biosciences and Environment, Faculty of Sciences and Techniques, Mohammedia- University Hassan II of Casablanca

Jul 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	.;.;D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.9	.;.;L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.2	.;.;.;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0020	.;.;.;D
Polyphen		1.0	.;.;D;.
MutPred		0.97		Loss of methylation at K591 (P = 0.1346);.;Loss of methylation at K591 (P = 0.1346);.;
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs794729219; hg19: chr7-140453152; COSMIC: COSV56127790;