rs180177035

Positions:

chr7-140801502-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PS2PP2PP3PM1PS3

This summary comes from the ClinGen Evidence Repository: The c.770A>G (p.Gln257Arg) variant in BRAF has been reported in the literature as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID:18042262, PMID:17551924, PMID:16474404). In vitro functional studies provide some evidence that the p.Q257R variant may impact protein function (PS3; PMID:18413255; PMID:19376813). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). Furthermore, this variant is located in exon 6, which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID:29493581). Computational prediction tools and conservation analysis suggest that the p.Q257R variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for cardio-facio-cutaneous syndrome in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PS3, PS2_VeryStrong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA222583/MONDO:0015280/004

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

BRAF
NM_001374258.1 missense

Scores

11

5

3

Clinical Significance

Pathogenic reviewed by expert panel P:32O:2

Conservation

PhyloP100: 7.97

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PS2

For more information check the summary or visit ClinGen Evidence Repository.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

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/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1 linkuse as main transcript	c.770A>G	p.Gln257Arg	missense_variant	6/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6 linkuse as main transcript	c.770A>G	p.Gln257Arg	missense_variant	6/18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2 linkuse as main transcript	c.770A>G	p.Gln257Arg	missense_variant	6/20		NM_001374258.1	ENSP00000496776
BRAF	ENST00000646891.2 linkuse as main transcript	c.770A>G	p.Gln257Arg	missense_variant	6/18		NM_004333.6	ENSP00000493543	P4

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.84e-7

AC:

1

AN:

1461672

Hom.:

0

Cov.:

31

AF XY:

0.00000138

AC XY:

1

AN XY:

727140

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:32Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 19, 2022	The BRAF c.770A>G, p.Gln257Arg variant (rs180177035) has been reported in multiple patients diagnosed with LEOPARD syndrome, cardio-facial-cutaneous syndrome or other RASopathies (Niihori 2006, Rodriguez-Viciana 2006, Gripp 2007, Narumi 2007, Nystrom 2008, Neumann 2009, Sarkozy 2009, Carcavilla 2013, Wong Ramsey 2014). The variant is located in the cysteine-rich domain of the BRAF conserved region 1 (Niihori 2006, Rodriguez-Viciana 2006), and several additional variants in neighboring codons have also been identified in cardio-facial-cutaneous syndrome (Kiel 2014). Functional analyses of the p.Gln257Arg variant protein indicates over-activation of phospho-MEK and phospho-ERK (Rodriguez-Viciana 2006, Rodriguez-Viciana 2008) and downstream transcriptional activity (Niihori 2006), consistent with the established disease mechanisms of BRAF-related disorders. This variant is reported in ClinVar (Variation ID: 13973) and is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamine at codon 257 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.838). Based on available information, this variant is considered to be pathogenic. References: Carcavilla A et al. LEOPARD syndrome: a variant of Noonan syndrome strongly associated with hypertrophic cardiomyopathy. Rev Esp Cardiol (Engl Ed). 2013 May;66(5):350-6. PMID: 24775816. Gripp KW et al. Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome. Am J Med Genet A. 2007 Jul 1;143A(13):1472-80. PMID: 17551924.. Kiel C et al. Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations. Mol Syst Biol. 2014 May 6;10(5):727. PMID: 24803665. Narumi Y et al. Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome. Am J Med Genet A. 2007 Apr 15;143A(8):799-807. PMID: 17366577. Niihori T et al. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet. 2006 Mar;38(3):294-6. PMID: 16474404. Nystrom AM et al. Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders. J Med Genet. 2008 Aug;45(8):500-6. PMID: 18456719. Rodriguez-Viciana P et al. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science. 2006 Mar 3;311(5765):1287-90. PMID: 16439621. Rodriguez-Viciana P et al. Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome. Methods Enzymol. 2008;438:277-89. PMID: 18413255. Sarkozy A et al. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat. 2009 Apr;30(4):695-702. PMID: 19206169. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 21, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	May 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2022	Functional in vitro studies have demonstrated that the p.(Q257R) variant results in increased kinase activity and activation of downstream effectors (MEK and ERK) (Rodriguez-Viciana et al., 2008), and in vivo studies have demostrated developmental defects and CFC-like features in animal models (Anastasaki et al., 2009; Moriya et al., 2015); Missense variants in this gene are often considered pathogenic (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17551924, 29778030, 29704308, 34573299, 17703371, 23312806, 16474404, 18042262, 19376813, 26472072, 26242988, 28809097, 27799561, 28650561, 29084544, 23340054, 30050098, 32005694, 32369273, 29907801, 33482860, 31130284, 27322245, 24719372, 24803665, 24775816, 33795686, 33040082, 33726816, 31785789, 33860439, 18413255, 29493581, 17603483, 15520807, 16439621, 15488754, 24957944) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 26, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Aug 22, 2017	- -

Cardiofaciocutaneous syndrome 1

Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	Jan 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with LEOPARD syndrome 3 (MIM#613707), cardiofaciocutaneous syndrome (MIM#115150) and Noonan syndrome 7 (MIM#613706) (PMID: 28783719, PMID: 29540830). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions or uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is a well established pathogenic variant associated with RASopathy or cardio-facial-cutaneous syndrome (ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cardio-facio-cutaneous syndrome

Pathogenic:3Other:2

Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The c.770A>G (p.Gln257Arg) variant in BRAF has been reported in the literature as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID:18042262, PMID:17551924, PMID:16474404). In vitro functional studies provide some evidence that the p.Q257R variant may impact protein function (PS3; PMID:18413255; PMID:19376813). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). Furthermore, this variant is located in exon 6, which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID:29493581). Computational prediction tools and conservation analysis suggest that the p.Q257R variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for cardio-facio-cutaneous syndrome in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PS3, PS2_VeryStrong. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2017	Variant summary: The BRAF c.770A>G (p.Gln257Arg) variant involves the alteration of a conserved nucleotide, is predicted to be damaging by 3/4 in silico tools (SNPs&GO not captured due to low reliability index) and is located in acylglycerol/phorbol-ester binding domain of the protein (InterPro). This variant is absent from 118580 control chromosomes from ExAC dataset. The variant is widely accepted to be pathogenic in the literature with concordant clinical and functional data. It is frequently reported in patients with CFC including evidence of de novo occurrences. In vitro as well as in vivo functional evidences are consistent with pathogenic outcome. Several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect - CFC International	-	Variant identified in multiple registry participants. Variant interpreted as Pathogenic and reported, most recently on 04-27-2016 by lab or GTR ID GeneDx. Variant interpreted as Pathogenic and reported on 09-25-2012 by lab or GTR ID Central Manchester University Hospitals Regional Genetics Laboratory Services. Variant interpreted as Pathogenic and reported on 04-30-2009 by lab or GTR ID Prevention Genetics. GenomeConnect - CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 01, 2015	The p.Gln257Arg variant in BRAF is an established pathogenic variant for Cardiof aciocutaneous syndrome (CFC) and is absent from large population studies. The p. Gln257Arg variant is one of the most commonly identified variants in BRAF and ha s been reported in >30 individuals with CFC syndrome (Rodriguez-Viciana 2008, Sa rkozy 2009, Neumann 2009, Abe 2012 Luk 2013, Wong Ramsey 2014, LMM unpublished d ata) and in 1 individual with LEOPARD syndrome (Carcavilla 2013). De novo occurr ences have been described for several individuals (Gripp 2007, Sarkozy 2009, Luk 2013, Neumann 2009, Niihori 2006). In addition, in vitro and in vivo functional studies support that this variant impacts protein function (Anastaski 2009, Ana stasaki 2012, Wen 2013, Inoue 2014). In summary, this variant meets our criteria to be classified as pathogenic for CFC syndrome in an autosomal dominant manner based upon de novo occurrence, absence from controls, and functional evidence. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Noonan syndrome 7

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Mar 21, 2022	ACMG classification criteria: PS2 strong, PS3 supporting, PS4 strong, PM1 moderated, PM2 moderated, PP1 supporting, PP3 supporting -
Pathogenic, no assertion criteria provided	clinical testing	Center for Molecular Medicine, Children’s Hospital of Fudan University	Feb 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jun 16, 2023	ACMG criteria used: PS3, PS4, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jul 22, 2020	- -

Noonan syndrome 1

Pathogenic:3

Pathogenic, no assertion criteria provided	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics, Centre for Human Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.770A>G;p.(Gln257Arg) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13973; OMIM: 164757.0013; PMID:18042262; 17551924; 16474404; 17703371; 24719372; 24775816) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID:18413255; 19376813; 16474404) - PS3_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (C1_1; PMID: 29493581) - PM1. This variant is not present in population databases (rs180177035, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 40351) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID:18042262; 17551924) - PM6_strong. Missense variant in BRAF that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

RASopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 19, 2023	Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt BRAF function. ClinVar contains an entry for this variant (Variation ID: 13973). This missense change has been observed in individuals with Noonan spectrum disorders (PMID: 16474404, 17703371, 24719372, 24775816). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 257 of the BRAF protein (p.Gln257Arg). Experimental studies have shown that this missense change affects BRAF function (PMID: 16474404, 18413255). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 11, 2013	This variant has been previously reported as disease-causing and was found once in our laboratory as a de novo change in a 24-year-old female with intellectual disability, epilepsy, coarse facial features, short stature, microcephaly, and severe brain ischemia and hemiparesis following cardiac arrest at age 8y. -

Noonan syndrome 7;C3150971:LEOPARD syndrome 3;CN029449:Cardiofaciocutaneous syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Aug 13, 2019

BRAF NM_004333.4 exon 6 p.Gln257Arg (c.770A>G): This variant is considered to be a common disease variant and has been reported in the literature in several individuals with cardiofaciocutaneous syndrome (CFC) and other Noonan-spectrum disorders, including several de novo occurrences (Niihori 2006 PMID:16474404, Gripp 2007 PMID:17551924, Schulz 2008 PMID:18042262, Sarkozy 2009 PMID:19206169, Neumann 2009 PMID:18854871, Carcavilla 2013 PMID:24775816, Wong Ramsey 2014 PMID:24719372, Joyce 2016 PMID:26242988, Xu 2017 PMID:29084544). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic, including an entry from the ClinGen RASopathies Expert Panel (Variation ID:13973). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, both in vitro and in vivo functional studies support that this variant will impact the protein (Niihori 2006 PMID:16474404, Rodriguez-Viciana 2008 PMID:18403255, Anastasaki 2009 PMID:19376813, Inoue 2014 PMID:25035421). In summary, this variant is classified as pathogenic based on the data above. -

BRAF-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 18, 2024

The BRAF c.770A>G variant is predicted to result in the amino acid substitution p.Gln257Arg. This variant has been reported in more than 14 unrelated individuals with RASopathies (Niihori et al 2006. PubMed ID: 16474404; Aeby et al 2007. PubMed ID: 17703371). In at least six individuals the variant likely occurred as a de novo event (Niihori et al. 2006. PubMed ID: 16474404; Gripp et al. 2007. PubMed ID: 17551924; Schulz et al. 2008. PubMed ID: 18042262). Functional studies demonstrate the p.Gln257Arg variant leads to increased p-MEK/ERK levels, consistent with a gain-of-function mechanism that results in the hyperactivation of the RAS pathway (Rodriguez-Viciana and Rauen. 2008. PubMed ID: 18413255; Anastasaki et al. 2009. PubMed ID: 19376813). Additionally, a different amino acid substitution (p.Gln257Lys) affecting the same amino acid has been reported as pathogenic (Narumi et al. 2007. PubMed ID: 17366577). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been interpreted by multiple clinical labs as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/13973/). This variant is interpreted as pathogenic. -

LEOPARD syndrome 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 02, 2019

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2024

The p.Q257R pathogenic mutation (also known as c.770A>G), located in coding exon 6 of the BRAF gene, results from an A to G substitution at nucleotide position 770. The glutamine at codon 257 is replaced by arginine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with features consistent with BRAF-related RASopathy, including several de novo occurrences (Niihori T et al. Nat Genet, 2006 Mar;38:294-6; Gripp KW et al. Am J Med Genet A, 2007 Jul;143A:1472-80; Wong Ramsey KN et al. Am J Med Genet A, 2014 Aug;164A:2036-42; Joyce S et al. Eur J Hum Genet, 2016 May;24:690-6; Mucciolo M et al. Int J Mol Sci, 2016 Jun;17; Mellis R et al. BJOG, 2022 Jan;129:52-61). In an assay testing BRAF function, this variant showed a functionally abnormal result (Rodriguez-Viciana P et al. Methods Enzymol, 2008;438:277-89). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Lung cancer;C0346629:Colorectal cancer;C1835047:Melanoma, cutaneous malignant, susceptibility to, 1;C3150970:Noonan syndrome 7;C3150971:LEOPARD syndrome 3;CN029449:Cardiofaciocutaneous syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

BRAF NM_004333.4 exon 6 p.Gln257Arg (c.770A>G): This variant is considered to be a common disease variant and has been reported in the literature in several individuals with cardiofaciocutaneous syndrome (CFC) and other Noonan-spectrum disorders, including several de novo occurrences (Niihori 2006 PMID:16474404, Gripp 2007 PMID:17551924, Schulz 2008 PMID:18042262, Sarkozy 2009 PMID:19206169, Neumann 2009 PMID:18854871, Carcavilla 2013 PMID:24775816, Wong Ramsey 2014 PMID:24719372, Joyce 2016 PMID:26242988, Xu 2017 PMID:29084544). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic, including an entry from the ClinGen RASopathies Expert Panel (Variation ID:13973). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, both in vitro and in vivo functional studies support that this variant will impact the protein (Niihori 2006 PMID:16474404, Rodriguez-Viciana 2008 PMID:18403255, Anastasaki 2009 PMID:19376813, Inoue 2014 PMID:25035421). In summary, this variant is classified as pathogenic based on the data above. -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.50

D

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

28

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

.;.;D;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Uncertain

0.24

D

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Pathogenic

1.0

D

MutationAssessor

Pathogenic

3.1

.;.;M;.

MutationTaster

Benign

1.0

A

PrimateAI

Pathogenic

0.88

D

PROVEAN

Benign

-0.98

.;.;.;N

REVEL

Pathogenic

0.84

Sift

Uncertain

0.022

.;.;.;D

Sift4G

Benign

0.25

.;.;.;T

Polyphen

0.96

.;.;D;.

Vest4

0.92

MutPred

0.91

Gain of MoRF binding (P = 0.0136);Gain of MoRF binding (P = 0.0136);Gain of MoRF binding (P = 0.0136);Gain of MoRF binding (P = 0.0136);

MVP

0.99

MPC

1.3

ClinPred

0.95

D

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

1.0

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs180177035; hg19: chr7-140501302;