rs727502902

Positions:

• chr7-140753338-T-TGTA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM4_Supporting PP3 PP5_Very_Strong

The NM_004333.6(BRAF):​c.1794_1796dupTAC​(p.Thr599dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_004333.6 disruptive_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 9.91

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 14 ACMG points.

• PM1: In a domain Protein kinase (size 260) in uniprot entity BRAF_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) in NM_004333.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004333.6. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 7-140753338-T-TGTA is Pathogenic according to our data. Variant chr7-140753338-T-TGTA is described in ClinVar as [Pathogenic]. Clinvar id is 162793.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.1914_1916dupTAC	p.Thr639dup	disruptive_inframe_insertion	16/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1794_1796dupTAC	p.Thr599dup	disruptive_inframe_insertion	15/18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1914_1916dupTAC	p.Thr639dup	disruptive_inframe_insertion	16/20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1794_1796dupTAC	p.Thr599dup	disruptive_inframe_insertion	15/18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2019	- -

Non-small cell lung carcinoma;C0009404:Neoplasm of the large intestine Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 20, 2013

The Thr599dup variant has been observed in a number of tumor types, including an aplastic thyroid carcinoma, melanoma, pancreatic adenocarcinoma and pilocytic as trocytomas (Jones 2009, Kubo 2009, Yu 2009, Eisenhardt 2011, Gauchotte 2011, Lon g 2011, Menzies 2012). In addition, it has been reported to have similar kinase activity as the BRAF Val600Glu variant (Eisenhardt 2011). -

Childhood ganglioglioma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute for Genomic Medicine, Nationwide Children's Hospital

Oct 09, 2017

The duplication of three nucleotides (c.1794_1796TAC) is a nonframeshift variant that results in addition of a Threonine residue between Thr599 and Val600 in BRAF. In vitro studies of this variant demonstrated an increased kinase activity and cellular MEK/ERK activation potential comparable to that of BRAF V600E (Eisenhardt et al., 2011). Presumably, the insertion of an additional Threonine residue at this position destabilizes the inactive conformation of the BRAF kinase domain. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727502902; hg19: chr7-140453138;