rs180177036

Variant names:

• chr7-140778053-C-A
• rs180177036
• NM_001374258.1:c.1575G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-140778053-C-A
• chr7-140778053-C-G
• chr7-140778053-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS4 PS3 PM2 PP3 PP2 PM6_Strong

This summary comes from the ClinGen Evidence Repository: The c.1455G>T (p.Leu485Phe) variant in BRAF is absent from gnomAD (PM2). It has been detected in at least 5 patients with clinical features of a RASopathy, 2 of which were reported as unconfirmed de novo cases (PS4; PM6_Strong; PMIDs: 18039235, 28524057, SCV000832735.1, SCV000204150.4, SCV000965953.1, Otto-von-Guericke-Universität Magdeburg internal communication). In vitro functional studies provide some evidence that the p.L485F variant may impact protein function (PS3; PMID:18413255). 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). Additionally, computational prediction tools and conservation analysis suggest that this variant may affect the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PM6_Strong, PS3, PM2, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA280060/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 5.00

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]

ENSG00000289788 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1575G>T	p.Leu525Phe	missense_variant	Exon 13 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1455G>T	p.Leu485Phe	missense_variant	Exon 12 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1575G>T	p.Leu525Phe	missense_variant	Exon 13 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1455G>T	p.Leu485Phe	missense_variant	Exon 12 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Pathogenic:2

Sep 08, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 485 of the BRAF protein (p.Leu485Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This missense change has been observed in individuals with cardio-facio-cutaneous syndrome (PMID: 16439621, 16474404, 18039235, 19206169, 28524057). ClinVar contains an entry for this variant (Variation ID: 177844). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects BRAF function (PMID: 16439621, 16474404, 18413255, 25348715). For these reasons, this variant has been classified as Pathogenic. -

Feb 27, 2020

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1455G>T (p.Leu485Phe) variant in BRAF is absent from gnomAD (PM2). It has been detected in at least 5 patients with clinical features of a RASopathy, 2 of which were reported as unconfirmed de novo cases (PS4; PM6_Strong; PMIDs: 18039235, 28524057, SCV000832735.1, SCV000204150.4, SCV000965953.1, Otto-von-Guericke-Universität Magdeburg internal communication). In vitro functional studies provide some evidence that the p.L485F variant may impact protein function (PS3; PMID: 18413255). 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). Additionally, computational prediction tools and conservation analysis suggest that this variant may affect the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PM6_Strong, PS3, PM2, PP2, PP3. -

Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome Pathogenic:1

Oct 21, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1455G>T (Leu485Phe) variant in BRAF has been previously identified in one individual with clinical features of a Cardio-facio-cutaneous syndrome (LMM unpu blished data). It was absent from large population studies (http://evs.gs.washin gton.edu/EVS/). In addition, a different variant with the same amino acid change (c.1455G>C) was identified in four individuals with clinical features of a RASo pathy (Niihori 2006, Rodriguez-Viciana 2006, LMM unpublished data). In vitro fu nctional studies provide some evidence that the Leu485Phe variant may impact pro tein function by increasing its kinase activity (Rodriguez-Viciana 2008). Howeve r, these types of assays may not accurately represent biological function. In s ummary, this variant meets our criteria to be classified as pathogenic (http://p cpgmwww.partners.org/personalizedmedicince/LMM). -

Cardiofaciocutaneous syndrome 1 Pathogenic:1

May 16, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS1, PS4, PM1, PM2, PP3, PP5- The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 177844). In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. It is not present in population databases (gnomAD no frequency). -

Cardio-facio-cutaneous syndrome Pathogenic:1

Sep 11, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRAF c.1455G>T (p.Leu485Phe) results in a non-conservative amino acid change located in the Serine-threonine/tyrosine-protein kinase, catalytic domain (IPR001245) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251326 control chromosomes (gnomAD). The variant, c.1455G>T, has been reported in the literature in individuals affected with Cardiofaciocutaneous Syndrome (Rodriguez-Viciana_2006, Sato_2017). Another variant (c.1455G>C) leading to the same protein change (p.Leu485Phe) has also been observed in individuals affected with Cardiofaciocutaneous Syndrome including one de novo occurrence (Niihori_2006, Sarkozy_2009). These data indicate that the variant is likely to be associated with disease. At least two publications reported experimental evidence evaluating an impact on protein function and showed increased BRAF activity (Niihori_2006, Rodriguez-Viciana_2006). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Another variant affecting the same codon, p.L485S, has been reported to associate with Cardiofaciocutaneous Syndrome too. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Jan 23, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in probands with clinical features of cardio-facio-cutaneous (CFC) syndrome (Yoon et al., 2007; Sato et al., 2017; Mohan et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 34358384, 30406758, 18039235, 28524057) -

Noonan syndrome Uncertain:1

-

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;.;D;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.1	.;.;L;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.8	.;.;.;N
REVEL	Pathogenic	0.76
Sift	Benign	0.20	.;.;.;T
Polyphen		0.26	.;.;B;.
MutPred		0.86		Gain of catalytic residue at L485 (P = 0.046);.;Gain of catalytic residue at L485 (P = 0.046);.;
MVP		0.99
MPC		2.1
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.95
gMVP		0.81

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: rs180177036; hg19: chr7-140477853; COSMIC: COSV56396779; COSMIC: COSV56396779;