rs201481342
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
This summary comes from the ClinGen Evidence Repository: The c.1024A>G (p.Ile342Val) variant in BRAF has been identified in 0.005644% (2/35438) of Latino chromosomes in gnomAD v2.1.1. This variant has been observed in several individuals whose clinical presentations lacked clear associations with a RASopathy (Invitae internal data, SCV000820707.1; Fulgent internal data; Baylor internal data; Greenwood Genetic Center internal data). Of note, this variant has also been seen in apparently unaffected parental samples (n=8) evaluated during whole exome sequencing suggesting that this variant may be likely benign; however, these cases were not well-phenotyped and therefore do not meet current requirements for BS2 (BS2 not met; GeneDx internal data, SCV000617143.2). Computational prediction tools and conservation analyses do not provide strong support for pathogenicity given the disease mechanism. In summary, the clinical significance of this variant is uncertain. LINK:https://erepo.genome.network/evrepo/ui/classification/CA4516829/MONDO:0021060/004
Frequency
Consequence
NM_001374258.1 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRAF | NM_001374258.1 | c.1024A>G | p.Ile342Val | missense_variant | 8/20 | ENST00000644969.2 | |
BRAF | NM_004333.6 | c.1024A>G | p.Ile342Val | missense_variant | 8/18 | ENST00000646891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRAF | ENST00000644969.2 | c.1024A>G | p.Ile342Val | missense_variant | 8/20 | NM_001374258.1 | |||
BRAF | ENST00000646891.2 | c.1024A>G | p.Ile342Val | missense_variant | 8/18 | NM_004333.6 | P4 | ||
ENST00000700122.1 | n.642T>C | non_coding_transcript_exon_variant | 3/4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 151978Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251454Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135898
GnomAD4 exome AF: 0.0000568 AC: 83AN: 1461862Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36AN XY: 727234
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152096Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74372
ClinVar
Submissions by phenotype
RASopathy Uncertain:2
Uncertain significance, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Mar 19, 2020 | The c.1024A>G (p.Ile342Val) variant in BRAF has been identified in 0.005644% (2/35438) of Latino chromosomes in gnomAD v2.1.1. This variant has been observed in several individuals whose clinical presentations lacked clear associations with a RASopathy (Invitae internal data, SCV000820707.1; Fulgent internal data; Baylor internal data; Greenwood Genetic Center internal data). Of note, this variant has also been seen in apparently unaffected parental samples (n=8) evaluated during whole exome sequencing suggesting that this variant may be likely benign; however, these cases were not well-phenotyped and therefore do not meet current requirements for BS2 (BS2 not met; GeneDx internal data, SCV000617143.2). Computational prediction tools and conservation analyses do not provide strong support for pathogenicity given the disease mechanism. In summary, the clinical significance of this variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 18, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 342 of the BRAF protein (p.Ile342Val). This variant is present in population databases (rs201481342, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with BRAF-related conditions. ClinVar contains an entry for this variant (Variation ID: 359048). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt BRAF function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Noonan syndrome 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Lung cancer;C0346629:Colorectal cancer;C1835047:Melanoma, cutaneous malignant, susceptibility to, 1;C3150970:Noonan syndrome 7;C3150971:LEOPARD syndrome 3;C4551602:Noonan syndrome 1;CN029449:Cardiofaciocutaneous syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 13, 2021 | - - |
LEOPARD syndrome 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 02, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at