NM_004333.6(BRAF):c.1858A>G (p.Met620Val) AND Noonan syndrome 7

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 27, 2022
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:: RCV002254850.4

Allele description [Variation Report for NM_004333.6(BRAF):c.1858A>G (p.Met620Val)]

NM_004333.6(BRAF):c.1858A>G (p.Met620Val)

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.1858A>G (p.Met620Val)

HGVS:

NC_000007.14:g.140753277T>C
NG_007873.3:g.176488A>G
NM_001354609.2:c.1858A>G
NM_001374244.1:c.1978A>G
NM_001374258.1:c.1978A>G
NM_001378467.1:c.1867A>G
NM_001378468.1:c.1858A>G
NM_001378469.1:c.1792A>G
NM_001378470.1:c.1756A>G
NM_001378471.1:c.1747A>G
NM_001378472.1:c.1702A>G
NM_001378473.1:c.1702A>G
NM_001378474.1:c.1858A>G
NM_001378475.1:c.1594A>G
NM_004333.6:c.1858A>GMANE SELECT
NP_001341538.1:p.Met620Val
NP_001361173.1:p.Met660Val
NP_001361187.1:p.Met660Val
NP_001365396.1:p.Met623Val
NP_001365397.1:p.Met620Val
NP_001365398.1:p.Met598Val
NP_001365399.1:p.Met586Val
NP_001365400.1:p.Met583Val
NP_001365401.1:p.Met568Val
NP_001365402.1:p.Met568Val
NP_001365403.1:p.Met620Val
NP_001365404.1:p.Met532Val
NP_004324.2:p.Met620Val
LRG_299t1:c.1858A>G
LRG_299:g.176488A>G
NC_000007.13:g.140453077T>C
NM_004333.4:c.1858A>G

Protein change:

M532V

Links:

dbSNP: rs1296245849

NCBI 1000 Genomes Browser:

rs1296245849

Molecular consequence:

NM_001354609.2:c.1858A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374244.1:c.1978A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374258.1:c.1978A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378467.1:c.1867A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378468.1:c.1858A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378469.1:c.1792A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378470.1:c.1756A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378471.1:c.1747A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378472.1:c.1702A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378473.1:c.1702A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378474.1:c.1858A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378475.1:c.1594A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004333.6:c.1858A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Noonan syndrome 7 (NS7)
Identifiers:: MONDO: MONDO:0013379; MedGen: C3150970; Orphanet: 648; OMIM: 613706

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ITGA2B [Ursus americanus]
ITGA2B [Ursus americanus]
Gene ID:123803148

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002525989	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Uncertain significance (Jan 27, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002525989

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

criteria provided, single submitter

(St. Jude Assertion Criteria 2020)

Uncertain significance
(Jan 27, 2022)

germline

clinical testing

Citation Link

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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

Details of each submission

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV002525989.2

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

Description

The BRAF c.1858A>G (p.Met620Val) missense variant is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/ ). This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PP2; PMID: 27535533). Seven of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in individuals with Cardiofaciocutaneous syndrome and Noonan syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria, as specified by the RASopathy Variant Curation Expert Panel (PMID:29493581): PM2_Supporting, PP3, PP2.

#	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: Dec 24, 2023

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