7-140754187-T-G

Position:

• chr7-140754187-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_004333.6(BRAF):​c.1741A>C​(p.Asn581His) variant causes a missense, splice region 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N581D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_004333.6 missense, splice_region
• Scores: Splicing: ADA: 0.2410
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.85

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]

BRAF (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a helix (size 2) in uniprot entity BRAF_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_004333.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-140754187-T-C is described in Lovd as [Pathogenic].
• 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 4.9447 (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, 0.989
• PP5: Variant 7-140754187-T-G is Pathogenic according to our data. Variant chr7-140754187-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55794.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1861A>C	p.Asn621His	missense_variant, splice_region_variant	15/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1741A>C	p.Asn581His	missense_variant, splice_region_variant	14/18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1861A>C	p.Asn621His	missense_variant, splice_region_variant	15/20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1741A>C	p.Asn581His	missense_variant, splice_region_variant	14/18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

BRAF-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2022

The BRAF c.1741A>C variant is predicted to result in the amino acid substitution p.Asn581His. This variant was reported as de novo in a patient with nonimmune hydrops fetalis (Sparks et al. 2020. PubMed ID: 33027564). A different variant at this position (p.Asn581Asp) has been reported in at least at least 14 individuals with cardio-facio-cutaneous syndrome, including at least 3 de novo events (Table S1, Rodriguez-Viciana et al. 2006. PubMed ID: 16439621; Niihori et al. 2006. PubMed ID: 16474404; Yoon et al. 2007. PubMed ID: 18039235; Schulz et al. 2007. PubMed ID: 18042262; Nava et al. 2007. PubMed ID: 17704260; Pierpont et al. 2010. PubMed ID: 20186801; Hazan et al. 2012. PubMed ID: 22876591; Quaio et al. 2013. PubMed ID: 24037001; Ciara et al. 2015. PubMed ID: 25463315; Table S3 - Leach et al. 2018. PubMed ID: 29907801). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

RASopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;.;D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.2	.;.;M;.
PrimateAI	Pathogenic	0.85	D
REVEL	Pathogenic	0.91
Polyphen		1.0	.;.;D;.
MutPred		0.96		Loss of ubiquitination at K578 (P = 0.0724);.;Loss of ubiquitination at K578 (P = 0.0724);.;
MVP		0.97
MPC		2.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.94
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.24
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 46

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

Publications

LitVar

Other links and lift over

dbSNP: rs180177040; hg19: chr7-140453987; COSMIC: COSV56077649;