rs397507456

chr7-140924640-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374258.1(BRAF):c.64G>A(p.Asp22Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,482,198 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D22E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00024 (3 hom.)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:10 O:1
• Conservation: PhyloP100: 2.38

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, BRAF
• BP4: Computational evidence support a benign effect (MetaRNN=0.007866472).
• BP6: Variant 7-140924640-C-T is Benign according to our data. Variant chr7-140924640-C-T is described in ClinVar as [Benign]. Clinvar id is 40335.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000298 (45/151046) while in subpopulation EAS AF= 0.00878 (44/5014). AF 95% confidence interval is 0.00672. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1	c.64G>A	p.Asp22Asn	missense_variant	1/20	ENST00000644969.2
BRAF	NM_004333.6	c.64G>A	p.Asp22Asn	missense_variant	1/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.64G>A	p.Asp22Asn	missense_variant	1/20		NM_001374258.1
BRAF	ENST00000646891.2	c.64G>A	p.Asp22Asn	missense_variant	1/18		NM_004333.6	P4

Frequencies

GnomAD3 genomes AF: 0.000305 AC: 46 AN: 150932 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00895

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000729 AC: 91 AN: 124868 Hom.: 0 AF XY: 0.000714 AC XY: 49 AN XY: 68586

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00881

Gnomad SAS exome AF: 0.0000902

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000257

GnomAD4 exome AF: 0.000245 AC: 326 AN: 1331152 Hom.: 3 Cov.: 24 AF XY: 0.000253 AC XY: 167 AN XY: 659446

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000812

Gnomad4 EAS exome AF: 0.00779

Gnomad4 SAS exome AF: 0.000154

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000869

Gnomad4 OTH exome AF: 0.000519

GnomAD4 genome AF: 0.000298 AC: 45 AN: 151046 Hom.: 0 Cov.: 31 AF XY: 0.000379 AC XY: 28 AN XY: 73822

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00878

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000491

ExAC AF: 0.0000322 AC: 1

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:10 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 17, 2017	Variant summary: The BRAF c.64G>A (p.Asp22Asn) variant involves the alteration of a conserved nucleotide and 2/4 in silico tools (SNPsandGO not captured due to low reliability index)predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 106/151790 control chromosomes, predominantly observed in East Asian subpopulation at a frequency of 0.009248 (102/11030). This frequency is about 3699 times the estimated maximal expected allele frequency of a pathogenic BRAF variant (0.0000025), suggesting this is likely a benign polymorphism found primarily in population(s) of East Asian origin. Multiple publications have cited the variant in individuals affected with various cancers indicated predominantly being a somatic occurrence, although limited information as to whether the variant was eliminated from being a germline occurrence was indicated. An internal LCA sample carrying this variant also carried another pathogenic variant PTPN11 p.Thr42Ala. Multiple clinical diagnostic laboratories have conflicting classifications "benign" or "uncertain significance." However, due the high occurrence in controls and the co-occurrence with a pathogenic PTPN11 variant, the variant of interest has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 12, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	BRAF: BS1 -

not specified Uncertain:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2015	proposed classification - variant undergoing re-assessment, contact laboratory -

RASopathy Benign:2

Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The variant c.64G>A (p.Asp22Asn) in BRAF was observed in a healthy adult individual who did not have clinical features of a RASopathy (BS2; Partners LMM and GeneDx internal data; GTR ID's: 21766, 26957; SCV000061615.5, SCV000057172.10). This variant has been observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder (BP2_Strong; LabCorp internal data GTR ID: 500026, ClinVar SCV000698345.1). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP2_S, BS2. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	- -

Noonan syndrome 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

LEOPARD syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jan 31, 2019

- -

BRAF-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2022

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Noonan syndrome and Noonan-related syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Benign	0.033
Eigen_PC	Benign	0.083
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.0079	T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.95	D
Polyphen		0.81	.;.;P;.;.
Vest4		0.38
MVP		0.67
MPC		0.92
ClinPred		0.13	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.41

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: rs397507456; hg19: chr7-140624440; COSMIC: COSV99071386;