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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:
RCV000521124.19

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
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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000616393ClinGen RASopathy Variant Curation Expert Panel
reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)		Likely pathogenic
(Apr 3, 2017) 		germlinecuration

Citation Link,

SCV000659072Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(May 13, 2022) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000659072.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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). 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. 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. ClinVar contains an entry for this variant (Variation ID: 40380). 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. This variant is not present in population databases (gnomAD no frequency).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 4, 2026

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