ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.1024A>G (p.Ile342Val) (rs201481342)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel 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 Clinical Services Laboratory,Illumina 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 Clinical Services Laboratory,Illumina 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.
Illumina Clinical Services Laboratory,Illumina RCV000302576 SCV000466988 likely benign Cardio-facio-cutaneous syndrome 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000521672 SCV000617143 likely benign not provided 2018-01-04 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000692862 SCV000820707 uncertain significance Rasopathy 2019-05-10 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 342 of the BRAF protein (p.Ile342Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs201481342, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRAF-related disease. ClinVar contains an entry for this variant (Variation ID: 359048). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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