rs397516904

Variant names:

• chr7-140801487-T-C
• rs397516904
• NM_001374258.1:c.785A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-140801487-T-C
• chr7-140801487-T-G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 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. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q262P) 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:4
• Conservation: PhyloP100: 7.97
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• cardiofaciocutaneous syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P, Genomics England PanelApp
• LEOPARD syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Noonan syndrome 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Genomics England PanelApp
• Noonan syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
• anaplastic astrocytoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 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 chr7-140801487-T-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 44831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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: 4.9008 (above the threshold of 3.09). GenCC associations: The gene is linked to cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome, cardiofaciocutaneous syndrome 1, Noonan syndrome 7, LEOPARD syndrome 3, anaplastic astrocytoma, Costello syndrome.
• 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 CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801487-T-C is described in CliVar as Pathogenic/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 rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.785A>G	p.Gln262Arg	missense_variant	Exon 6 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.785A>G	p.Gln262Arg	missense_variant	Exon 6 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.785A>G	p.Gln262Arg	missense_variant	Exon 6 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.785A>G	p.Gln262Arg	missense_variant	Exon 6 of 18		NM_004333.6	ENSP00000493543.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111934

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Apr 17, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jan 15, 2015

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Apr 10, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.785A>G (p.Q262R) alteration is located in exon 6 (coding exon 6) of the BRAF gene. This alteration results from an A to G substitution at nucleotide position 785, causing the glutamine (Q) at amino acid position 262 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals with features consistent with BRAF-related RASopathy (Nava, 2007; Denayer, 2010; Leach, 2019; Dell'Edera, 2020). Two other alterations at the same codon, c.785A>C (p.Q262P) and c.784C>A (p.Q262K), have been detected in patients with cardiofaciocutaneous syndrome (Schulz, 2008; Ciara, 2015). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

RASopathy Pathogenic:1

Aug 08, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
DEOGEN2	Uncertain	0.76	.;.;D;.
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
MutationAssessor	Benign	0.68	.;.;N;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.4	.;.;.;N
REVEL	Pathogenic	0.71
Sift	Benign	0.25	.;.;.;T
Sift4G	Benign	0.25	.;.;.;T
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
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397516904; hg19: chr7-140501287;