NM_004333.6(BRAF):c.2135C>A (p.Ala712Asp) AND RASopathy

Germline classification:
no classifications from unflagged records (1 submission)
Last evaluated:
Mar 15, 2024
Review status:
no classifications from unflagged records
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:
RCV001850036.7

Allele description [Variation Report for NM_004333.6(BRAF):c.2135C>A (p.Ala712Asp)]

NM_004333.6(BRAF):c.2135C>A (p.Ala712Asp)

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.2135C>A (p.Ala712Asp)
HGVS:
  • NC_000007.14:g.140734763G>T
  • NG_007873.3:g.195002C>A
  • NM_001354609.2:c.2135C>A
  • NM_001374244.1:c.2255C>A
  • NM_001374258.1:c.2255C>A
  • NM_001378467.1:c.2144C>A
  • NM_001378468.1:c.2127+5049C>A
  • NM_001378469.1:c.2069C>A
  • NM_001378470.1:c.2033C>A
  • NM_001378471.1:c.2024C>A
  • NM_001378472.1:c.1979C>A
  • NM_001378473.1:c.1979C>A
  • NM_001378474.1:c.2127+5049C>A
  • NM_001378475.1:c.1871C>A
  • NM_004333.6:c.2135C>AMANE SELECT
  • NP_001341538.1:p.Ala712Asp
  • NP_001361173.1:p.Ala752Asp
  • NP_001361187.1:p.Ala752Asp
  • NP_001365396.1:p.Ala715Asp
  • NP_001365398.1:p.Ala690Asp
  • NP_001365399.1:p.Ala678Asp
  • NP_001365400.1:p.Ala675Asp
  • NP_001365401.1:p.Ala660Asp
  • NP_001365402.1:p.Ala660Asp
  • NP_001365404.1:p.Ala624Asp
  • NP_004324.2:p.Ala712Asp
  • LRG_299t1:c.2135C>A
  • LRG_299:g.195002C>A
  • NC_000007.13:g.140434563G>T
  • NM_004333.4:c.2135C>A
Protein change:
A624D
Links:
dbSNP: rs727502904
NCBI 1000 Genomes Browser:
rs727502904
Molecular consequence:
  • NM_001378468.1:c.2127+5049C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001378474.1:c.2127+5049C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354609.2:c.2135C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374244.1:c.2255C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374258.1:c.2255C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378467.1:c.2144C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378469.1:c.2069C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378470.1:c.2033C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378471.1:c.2024C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378472.1:c.1979C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378473.1:c.1979C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378475.1:c.1871C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004333.6:c.2135C>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
No clinical assertions found. See "Flagged submissions" below.
Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002274194.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 162795). This variant has not been reported in the literature in individuals affected with BRAF-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 712 of the BRAF protein (p.Ala712Asp).

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

Flagged submissions

Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002274194Labcorp Genetics (formerly Invitae), Labcorp
flagged submission
Reason: Outlier claim with insufficient supporting evidence
Notes: Multiple other labs mention de novo internal cases, while Invitae mentions no case-level data.

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jun 4, 2022) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Last Updated: Oct 8, 2024