NM_004333.6(BRAF):c.83GCGCCG[1] (p.28GA[1]) AND RASopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 12, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000033270.8

Allele description [Variation Report for NM_004333.6(BRAF):c.83GCGCCG[1] (p.28GA[1])]

NM_004333.6(BRAF):c.83GCGCCG[1] (p.28GA[1])

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

7q34

Genomic location:

Preferred name:

NM_004333.6(BRAF):c.83GCGCCG[1] (p.28GA[1])

HGVS:

NC_000007.14:g.140924608GCCGGC[1]
NG_007873.3:g.5144GCGCCG[1]
NM_001354609.2:c.83GCGCCG[1]
NM_001374244.1:c.83GCGCCG[1]
NM_001374258.1:c.83GCGCCG[1]
NM_001378467.1:c.83GCGCCG[1]
NM_001378468.1:c.83GCGCCG[1]
NM_001378469.1:c.83GCGCCG[1]
NM_001378470.1:c.83GCGCCG[1]
NM_001378471.1:c.83GCGCCG[1]
NM_001378474.1:c.83GCGCCG[1]
NM_001378475.1:c.83GCGCCG[1]
NM_004333.4:c.89_100del12
NM_004333.6:c.83GCGCCG[1]MANE SELECT
NP_001341538.1:p.28GA[1]
NP_001361173.1:p.28GA[1]
NP_001361187.1:p.28GA[1]
NP_001365396.1:p.28GA[1]
NP_001365397.1:p.28GA[1]
NP_001365398.1:p.28GA[1]
NP_001365399.1:p.28GA[1]
NP_001365400.1:p.28GA[1]
NP_001365403.1:p.28GA[1]
NP_001365404.1:p.28GA[1]
NP_004324.2:p.28GA[1]
NP_004324.2:p.Gly30_Ala33del
LRG_299t1:c.89_100del12
LRG_299:g.5144GCGCCG[1]
NC_000007.13:g.140624404_140624415del
NC_000007.13:g.140624408GCCGGC[1]
NM_004333.4:c.89_100delGCGCCGGCGCCG
NM_004333.6:c.89_100delGCGCCGGCGCCGMANE SELECT
p.G30_A33delGAGA

Links:

dbSNP: rs397507458

NCBI 1000 Genomes Browser:

rs397507458

Molecular consequence:

NM_001354609.2:c.83GCGCCG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001374244.1:c.83GCGCCG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001374258.1:c.83GCGCCG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001378467.1:c.83GCGCCG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001378468.1:c.83GCGCCG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001378469.1:c.83GCGCCG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001378470.1:c.83GCGCCG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001378471.1:c.83GCGCCG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001378474.1:c.83GCGCCG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001378475.1:c.83GCGCCG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_004333.6:c.83GCGCCG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000057175	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Jan 29, 2014)	germline	clinical testing	Citation Link,
SCV001489359	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 12, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29907801, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000057175

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Jan 29, 2014)

germline

clinical testing

Citation Link,

SCV001489359

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 12, 2023)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions.

Leach NT, Wilson Mathews DR, Rosenblum LS, Zhou Z, Zhu H, Heim RA.

Genet Med. 2019 Feb;21(2):417-425. doi: 10.1038/s41436-018-0062-0. Epub 2018 Jun 15. Erratum in: Genet Med. 2018 Jul 26;:.

PubMed [citation]

PMID:: 29907801

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV000057175.4

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

Description

c.89_100del12: p.Gly30_Ala33delGlyAlaGlyAla (G30_A33delGAGA) in exon 1 of the BRAF gene (NM_004333.4)The c.89_100del12 in-frame deletion in the BRAF gene has not been reported as a disease-causing mutation, nor is it known to be a benign polymorphism to our knowledge. This deletion occurs in a region of the protein that is not highly conserved in mammals and no disease-causing mutation has been reported before codon Threonine 241. Most disease-causing mutations result in a gain-of-function. It is uncertain if this deletion would result in a gain-of-function, loss-of-function, or have no impact on protein function at all. Therefore, this variant cannot be interpreted for diagnosis or used for genetic counseling without further studies. The variant is found in NOONAN panel(s).

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

From Invitae, SCV001489359.4

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

Description

This variant, c.89_100del, results in the deletion of 4 amino acid(s) of the BRAF protein (p.Gly30_Ala33del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs397507458, gnomAD 0.05%). This variant has been observed in individual(s) with clinical features of BRAF-related conditions (PMID: 29907801). ClinVar contains an entry for this variant (Variation ID: 40222). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.

#	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: Mar 16, 2024

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