7-140753334-T-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001374258.1(BRAF):c.1921A>C(p.Lys641Gln) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K641N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.94

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 19 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001374258.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-140753333-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, BRAF
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant 7-140753334-T-G is Pathogenic according to our data. Variant chr7-140753334-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 41446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1	c.1921A>C	p.Lys641Gln	missense_variant	16/20	ENST00000644969.2
BRAF	NM_004333.6	c.1801A>C	p.Lys601Gln	missense_variant	15/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.1921A>C	p.Lys641Gln	missense_variant	16/20		NM_001374258.1
BRAF	ENST00000646891.2	c.1801A>C	p.Lys601Gln	missense_variant	15/18		NM_004333.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 18, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2021	Published functional studies of the K601Q variant have demonstrated that it results in the enhanced phosphorylation of MEK and ERK proteins (Sarkozy et al., 2009).; Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 19206169, 26619011, 16953233, 33753861, 24803665, 33040082, 33482860, 29493581, 17603483, 15520807, 16439621, 15488754, 24957944) -

Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 02, 2019

The p.Lys601Gln variant in BRAF has been identified as de novo occurrence in 3 i ndividuals with cardio-facio-cutaneous syndrome (Sarkozy 2009, LMM data). It was absent from large population studies. Computational prediction tools and in vit ro functional studies support an impact on protein function (Sarkozy 2009). The p.Lys601Gln variant has been observed as a somatic mutation in tumor specimens f rom colorectal cancer (Oliveira 2007) and melanoma (Long 2013). Furthermore, thi s variant is in the CR3 activation segment domain, which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF. Th is variant has also been reported in ClinVar (Variation ID #41446). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominan t cardio-facio-cutaneous syndrome. ACMG/AMP Criteria applied: PM6_Strong, PM1, P M2, PS4_Moderate, PS3_Supporting, PP3. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 20, 2023

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 601 of the BRAF protein (p.Lys601Gln). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Lys601 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22495831, 24451042, 28650561, 28832562). 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 function (PMID: 19206169). 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: 41446). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 19206169). In at least one individual the variant was observed to be de novo. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	29
Dann	Uncertain	0.99
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
Polyphen		0.99	.;.;D;.
MutPred		0.86		Loss of ubiquitination at K601 (P = 0.0183);.;Loss of ubiquitination at K601 (P = 0.0183);.;
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.86

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: rs121913364; hg19: chr7-140453134;