7-140754187-T-G

Variant names:

• chr7-140754187-T-G
• rs180177040
• NM_001374258.1:c.1861A>C

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]

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 the BRAF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 139 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 3.7208 (above the threshold of 3.09). Trascript score misZ: 4.9447 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1861A>C	p.Asn621His	missense_variant, splice_region_variant	Exon 15 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1741A>C	p.Asn581His	missense_variant, splice_region_variant	Exon 14 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1861A>C	p.Asn621His	missense_variant, splice_region_variant	Exon 15 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1741A>C	p.Asn581His	missense_variant, splice_region_variant	Exon 14 of 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

Dec 21, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;