NM_004333.6(BRAF):c.2265C>G (p.Ile755Met) AND RASopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 1, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001889037.6

Allele description [Variation Report for NM_004333.6(BRAF):c.2265C>G (p.Ile755Met)]

NM_004333.6(BRAF):c.2265C>G (p.Ile755Met)

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.2265C>G (p.Ile755Met)

HGVS:

NC_000007.14:g.140734633G>C
NG_007873.3:g.195132C>G
NM_001354609.2:c.2265C>G
NM_001374244.1:c.2385C>G
NM_001374258.1:c.2385C>G
NM_001378467.1:c.2274C>G
NM_001378468.1:c.2127+5179C>G
NM_001378469.1:c.2199C>G
NM_001378470.1:c.2163C>G
NM_001378471.1:c.2154C>G
NM_001378472.1:c.2109C>G
NM_001378473.1:c.2109C>G
NM_001378474.1:c.2127+5179C>G
NM_001378475.1:c.2001C>G
NM_004333.6:c.2265C>GMANE SELECT
NP_001341538.1:p.Ile755Met
NP_001361173.1:p.Ile795Met
NP_001361187.1:p.Ile795Met
NP_001365396.1:p.Ile758Met
NP_001365398.1:p.Ile733Met
NP_001365399.1:p.Ile721Met
NP_001365400.1:p.Ile718Met
NP_001365401.1:p.Ile703Met
NP_001365402.1:p.Ile703Met
NP_001365404.1:p.Ile667Met
NP_004324.2:p.Ile755Met
LRG_299:g.195132C>G
NC_000007.13:g.140434433G>C

Protein change:

I667M

Links:

dbSNP: rs763340034

NCBI 1000 Genomes Browser:

rs763340034

Molecular consequence:

NM_001378468.1:c.2127+5179C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001378474.1:c.2127+5179C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354609.2:c.2265C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374244.1:c.2385C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374258.1:c.2385C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378467.1:c.2274C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378469.1:c.2199C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378470.1:c.2163C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378471.1:c.2154C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378472.1:c.2109C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378473.1:c.2109C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378475.1:c.2001C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004333.6:c.2265C>G - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002155901	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 1, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002155901

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 1, 2021)

germline

clinical testing

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

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

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, SCV002155901.3

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

Description

This sequence change replaces isoleucine with methionine at codon 755 of the BRAF protein (p.Ile755Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. 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 not expected to disrupt BRAF protein function. This variant has not been reported in the literature in individuals with BRAF-related conditions. This variant is present in population databases (rs763340034, ExAC 0.01%).

#	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: Sep 29, 2024

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