NM_004333.6(BRAF):c.1595G>A (p.Cys532Tyr) AND RASopathy

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Apr 3, 2017
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000521124.17

Allele description [Variation Report for NM_004333.6(BRAF):c.1595G>A (p.Cys532Tyr)]

NM_004333.6(BRAF):c.1595G>A (p.Cys532Tyr)

Gene:

BRAF:B-Raf proto-oncogene, serine/threonine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q34

Genomic location:

Preferred name:

NM_004333.6(BRAF):c.1595G>A (p.Cys532Tyr)

Other names:

NM_004333.4(BRAF):c.1595G>A

HGVS:

NC_000007.14:g.140777011C>T
NG_007873.3:g.152754G>A
NM_001354609.2:c.1595G>A
NM_001374244.1:c.1715G>A
NM_001374258.1:c.1715G>A
NM_001378467.1:c.1604G>A
NM_001378468.1:c.1595G>A
NM_001378469.1:c.1529G>A
NM_001378470.1:c.1493G>A
NM_001378471.1:c.1484G>A
NM_001378472.1:c.1439G>A
NM_001378473.1:c.1439G>A
NM_001378474.1:c.1595G>A
NM_001378475.1:c.1331G>A
NM_004333.6:c.1595G>AMANE SELECT
NP_001341538.1:p.Cys532Tyr
NP_001361173.1:p.Cys572Tyr
NP_001361187.1:p.Cys572Tyr
NP_001365396.1:p.Cys535Tyr
NP_001365397.1:p.Cys532Tyr
NP_001365398.1:p.Cys510Tyr
NP_001365399.1:p.Cys498Tyr
NP_001365400.1:p.Cys495Tyr
NP_001365401.1:p.Cys480Tyr
NP_001365402.1:p.Cys480Tyr
NP_001365403.1:p.Cys532Tyr
NP_001365404.1:p.Cys444Tyr
NP_004324.2:p.Cys532Tyr
LRG_299t1:c.1595G>A
LRG_299:g.152754G>A
LRG_299p1:p.Cys532Tyr
NC_000007.13:g.140476811C>T
NM_004333.4:c.1595G>A

Protein change:

C444Y

Links:

dbSNP: rs397507479

NCBI 1000 Genomes Browser:

rs397507479

Molecular consequence:

NM_001354609.2:c.1595G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374244.1:c.1715G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374258.1:c.1715G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378467.1:c.1604G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378468.1:c.1595G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378469.1:c.1529G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378470.1:c.1493G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378471.1:c.1484G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378472.1:c.1439G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378473.1:c.1439G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378474.1:c.1595G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378475.1:c.1331G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004333.6:c.1595G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

Recent activity

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HD domain-containing protein [Paenimyroides ceti]
HD domain-containing protein [Paenimyroides ceti]
gi|2532951429|ref|WP_290361833.1|

Protein
c-type cytochrome [Paenimyroides ceti]
c-type cytochrome [Paenimyroides ceti]
gi|2532951431|ref|WP_290361835.1|

Protein
hypothetical protein [Paenimyroides ceti]
hypothetical protein [Paenimyroides ceti]
gi|2532954899|ref|WP_290365303.1|

Protein
OsmC family protein [Paenimyroides ceti]
OsmC family protein [Paenimyroides ceti]
gi|2532952687|ref|WP_290363091.1|

Protein
ARF GTPase-activating protein GIT2 isoform 21 [Mus musculus]
ARF GTPase-activating protein GIT2 isoform 21 [Mus musculus]
gi|2711571206|ref|NP_001416003.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000616393	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Likely pathogenic (Apr 3, 2017)	germline	curation	Citation Link,
SCV000659072	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (May 13, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31785789, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000616393

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)

Likely pathogenic
(Apr 3, 2017)

germline

curation

Citation Link,

SCV000659072

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(May 13, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders.

Turner TN, Wilfert AB, Bakken TE, Bernier RA, Pepper MR, Zhang Z, Torene RI, Retterer K, Eichler EE.

Am J Hum Genet. 2019 Dec 5;105(6):1274-1285. doi: 10.1016/j.ajhg.2019.11.003. Epub 2019 Nov 27.

PubMed [citation]

PMID:: 31785789
PMCID:: PMC6904808

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From ClinGen RASopathy Variant Curation Expert Panel, SCV000616393.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.1595G>A (p.Cys532Tyr) variant in BRAF has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; Partners LMM, GeneDx, EGL internal data; GTR ID's: 21766, 26957, 500060; SCV000112809.7, SCV000057229.13, SCV000197143.4). 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). Computational prediction tools and conservation analysis suggest that the p.Cys532Tyr variant may impact 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): PM6, PM2, PP2, PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000659072.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 532 of the BRAF protein (p.Cys532Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRAF-related conditions (PMID: 31785789; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40380). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRAF protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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