rs727504571

Positions:

• chr7-140808049-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

This summary comes from the ClinGen Evidence Repository: The c.622A>G (p.Ile208Val) variant in BRAF is present in 0.00001% (2/128934) European alleles in gnomAD. The computational predictor REVEL gives a score of 0.318, which is neither above nor below the thresholds predicting a damaging or benign impact on BRAF function. This variant was observed in two healthy adult individuals who did not have clinical features of a RASopathy (SCV000205449.5; PMID:29945942). Additionally, 12 apparently unaffected parental samples were observed with this variant (BS2; SCV000329576.8, SCV001011557.1). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BS2, PP2 (RASopathy VCEP specifications version 1; 8/11/22). LINK:https://erepo.genome.network/evrepo/ui/classification/CA183392/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:4
• Conservation: PhyloP100: 8.02

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 Likely_benign. Variant got -3 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1	c.622A>G	p.Ile208Val	missense_variant	5/20	ENST00000644969.2
BRAF	NM_004333.6	c.622A>G	p.Ile208Val	missense_variant	5/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.622A>G	p.Ile208Val	missense_variant	5/20		NM_001374258.1
BRAF	ENST00000646891.2	c.622A>G	p.Ile208Val	missense_variant	5/18		NM_004333.6	P4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251166 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1460448 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 726608

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74280

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Uncertain:1 Benign:1

Uncertain significance, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Mar 09, 2020	The c.622A>G (p.Ile208Val) variant in BRAF is present in 0.00001% (2/128934) European alleles in gnomAD. This variant was observed in two healthy adult individuals who did not have clinical features of a RASopathy (SCV000205449.5; PMID:29945942). Additionally, 12 apparently unaffected parental samples were observed with this variant, however this evidence does not meet current scoring criteria for BS2 at this time (BS2 not met; SCV000329576.8, SCV001011557.1). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the clinical significance of the p.Ile208Val variant is uncertain at this time. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jul 01, 2022	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 21, 2018	We observed the Ile208Val variant in BRAF in one individual with middle aortic s yndrome, low nasal bridge, hypertension, facial coarseness, short stature, learn ing disabilities/mental retardation, wide-spaced nipples and webbed neck and her reportedly unaffected parent, both tested by our laboratory. The variant was al so found in a fetus with increased nuchal translucency and her unaffected father (personal communication with the mother via our ClinVar entry). GeneDx observed the variant in three unrelated families undergoing exome testing in which the c linical presentations of individuals with the variant (n=6) were either normal o r had clinical features inconsistent with a RASopathy. This variant has also bee n found in the general population at a frequency of 3/276842 alleles (gnomAD, rs 727504571). Ile208Val has been reported in a melanoma cell line which also carri ed Val600Glu, a well-characterized activating mutation (Ikediobi 2006). Computat ional analyses (biochemical amino acid properties, conservation, AlignGVGD, Poly Phen2, and SIFT) do not provide strong support for or against an impact to the n ormal function of the protein. In summary, based upon the 3 observations in the general population and the 8 observations in individuals without a RASopathy dia gnosis, this variant is likely benign (Grant 2018). ACMG/AMP criteria applied: B S1_Supporting, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 06, 2019	Variant summary: BRAF c.622A>G (p.Ile208Val) results in a conservative amino acid change located in the Raf-like Ras-binding domain (IPR003116) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251166 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.622A>G has been reported in the literature in unaffected individuals and index cases with clinical features inconsistent with a RASopathy in families undergoing evaluation for Noonan Syndrome and Related Conditions (Grant_2018). The variant was also identified in the paternal specimen following its initial identification in a prenatal specimen undergoing evaluation for Noonan syndrome and Related conditions at our laboratory. These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. Co-occurrences with other pathogenic variant(s) have been reported in a melanoma cell line ( BRAF c.1799T>A, p.Val600Glu), providing supporting evidence for a benign role (Ikediobi_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Noonan syndrome and Noonan-related syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 21, 2019

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 05, 2019

This variant is associated with the following publications: (PMID: 29945942) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	0.98
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
Polyphen		0.45	.;.;B;.
Vest4		0.36
MutPred		0.63		Loss of methylation at K206 (P = 0.0929);Loss of methylation at K206 (P = 0.0929);Loss of methylation at K206 (P = 0.0929);Loss of methylation at K206 (P = 0.0929);
MVP		0.72
MPC		1.1
ClinPred		0.45	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.79

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: rs727504571; hg19: chr7-140507849;