Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000692862 | SCV001335310 | uncertain significance | RASopathy | 2020-03-19 | reviewed by expert panel | curation | 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. |
Illumina Laboratory Services, |
RCV000342225 | SCV000466986 | uncertain significance | LEOPARD syndrome 3 | 2018-01-13 | criteria provided, single submitter | clinical testing | 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. |
Illumina Laboratory Services, |
RCV000404519 | SCV000466987 | uncertain significance | Noonan syndrome 7 | 2018-01-13 | criteria provided, single submitter | clinical testing | 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. |
Gene |
RCV000521672 | SCV000617143 | likely benign | not provided | 2019-08-02 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000692862 | SCV000820707 | uncertain significance | RASopathy | 2023-11-18 | criteria provided, single submitter | clinical testing | 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. |
Fulgent Genetics, |
RCV005004139 | SCV002812869 | uncertain significance | Cardiofaciocutaneous syndrome 1; LEOPARD syndrome 3; Noonan syndrome 7; Melanoma, cutaneous malignant, susceptibility to, 1; Colorectal cancer; Lung cancer | 2024-05-13 | criteria provided, single submitter | clinical testing | |
Clinical Genomics Laboratory, |
RCV005051775 | SCV005685416 | uncertain significance | Cardiofaciocutaneous syndrome 1 | 2024-05-21 | criteria provided, single submitter | clinical testing | A BRAF c.1024A>G (p.Ile342Val) variant was identified at a near heterozygous allelic fraction of 47%, a frequency which may be consistent with it being of germline origin. This variant is observed on 92/1,613,958 alleles in the general population (gnomAD v.4.1.0). It has been reported in the ClinVar database as a germline variant of uncertain significance by five submitters, including an expert panel, and likely benign by one submitter (ClinVar ID: 359048). Computational predictors suggest that the variant does not impact BRAF function. The BRAF gene is defined by the ClinGen's RASopathy expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Gelb BD et al., PMID: 29493581). Due to limited information and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry (Gelb BD et al., PMID: 29493581), the clinical significance of this variant is uncertain at this time. |