rs397516904

chr7-140801487-T-Cchr7-140801487-T-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001374258.1(BRAF):c.785A>G(p.Gln262Arg) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q262K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.97

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 13 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-140801488-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40352.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, 0.932
• PP5: Variant 7-140801487-T-C is Pathogenic according to our data. Variant chr7-140801487-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180723.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.785A>G	p.Gln262Arg	missense_variant	6/20	ENST00000644969.2
BRAF	NM_004333.6	c.785A>G	p.Gln262Arg	missense_variant	6/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.785A>G	p.Gln262Arg	missense_variant	6/20		NM_001374258.1
BRAF	ENST00000646891.2	c.785A>G	p.Gln262Arg	missense_variant	6/18		NM_004333.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461728 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727168

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2023	Multiple missense variants at this residue [p.(Q262K) and p.(Q262P)] have been reported in association with BRAF-related RASopathy in patients previously tested at GeneDx and in the published literature (Ciara et al., 2015; Schulz et al., 2008); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24957944, 15488754, 16439621, 15520807, 17603483, 29493581, 24803665, 17704260, 19953625, 29907801, 30050098, 32185055, 25463315, 18042262) -

RASopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 08, 2015

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Likely Pathogenic. Two other missense substitutions at this codon (p.Gln262Lys and p.Gln262Pro) have been reported as de novo mutations in patients affected with cardio-facio-cutaenous syndrome (PMID: 18042262, 25463315). This suggests that the glutamine residue is important for BRAF protein function. This variant was reported in an individual affected with cardio-facio-cutaneous syndrome (PMID: 17704260) and in an individual affected with Noonan syndrome (PMID: 19953625). Full parental testing was not performed in either cases, but were suspected to be sporadic. This variant is not present in population databases and has been reported in the literature. ClinVar also contains an entry for this variant (RCV000157699). This sequence change replaces glutamine with arginine at codon 262 of the BRAF protein (p.Gln262Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.085	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.031	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
Polyphen		0.48	.;.;P;.
Vest4		0.90
MutPred		0.88		Gain of MoRF binding (P = 0.0298);Gain of MoRF binding (P = 0.0298);Gain of MoRF binding (P = 0.0298);Gain of MoRF binding (P = 0.0298);
MVP		0.99
MPC		1.6
ClinPred		0.93	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397516904; hg19: chr7-140501287;