rs121913366

Positions:

• chr7-140753345-A-C
• chr7-140753345-A-G
• chr7-140753345-A-T

Variant summary

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

The NM_001374258.1(BRAF):​c.1910T>G​(p.Leu637Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L637P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:6
• 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 12 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr7-140753346-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 13969.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, 0.945
• PP5: Variant 7-140753345-A-C is Pathogenic according to our data. Variant chr7-140753345-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13968.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1	c.1910T>G	p.Leu637Arg	missense_variant	16/20	ENST00000644969.2
BRAF	NM_004333.6	c.1790T>G	p.Leu597Arg	missense_variant	15/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.1910T>G	p.Leu637Arg	missense_variant	16/20		NM_001374258.1
BRAF	ENST00000646891.2	c.1790T>G	p.Leu597Arg	missense_variant	15/18		NM_004333.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460368 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726566

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: no assertion criteria provided

Submissions by phenotype

Prostate adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Multiple myeloma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lung adenocarcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 15, 2003

- -

Melanoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Ovarian neoplasm Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

Malignant melanoma of skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
Polyphen		1.0	.;.;D;.
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.99

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: rs121913366; hg19: chr7-140453145; COSMIC: COSV56121113;