ClinVar Miner

Submissions for variant NM_001374258.1(BRAF):c.83GCGCCG[4] (p.28GA[4]) (rs397507458)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157830 SCV000207760 uncertain significance Rasopathy 2013-12-27 criteria provided, single submitter clinical testing This mutation is denoted c.100_101insGCGCCG: p.Gly32_Ala33dup (G32_A33dup) in exon 1 of the BRAF gene. The normal sequence with the bases that are duplicated in braces is: GCGCCG{GCGCCG}CGGCCT(NM_004333.4). The c.100_101insGCGCCG in-frame insertion in the BRAF gene has not been reported as a disease-causing mutation, nor is it known to be a benign polymorphism to our knowledge. An in-frame deletion affecting these same nucleotides (c.95_100delGCGCCG) has been observed at GeneDx in one patient who also had a pathogenic mutation in the PTPN11 gene. This insertion occurs in a region of the protein that is not well conserved in mammals and no disease-causing mutation has been reported before codon Threonine 241. Most disease-causing mutations in the BRAF gene result in a gain-of-function. It is uncertain if this duplication would result in a gain-of-function, loss-of-function, or have no impact on protein function at all. Therefore, this result variant be interpreted for diagnosis or used for genetic counseling without further studies. The variant is found in NOONAN panel(s).
GeneDx RCV000484992 SCV000564707 uncertain significance not specified 2016-12-22 criteria provided, single submitter clinical testing To our knowledge, the c.95_100dupGCGCCG in-frame duplication in the BRAF gene has not been published as a pathogenic variant or reported as a benign variant. It was not observed in approximately 2,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.95_100dupGCGCCG variant results in an in-frame duplication of 2 amino acids and is not predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. As most pathogenic variants in the BRAF gene result in a gain-of-function, it is uncertain if this duplication would result in a gain-of-function, loss-of-function, or have no impact on protein function at all. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723548 SCV000700550 uncertain significance not provided 2013-03-18 criteria provided, single submitter clinical testing
Invitae RCV000157830 SCV000776850 uncertain significance Rasopathy 2020-08-27 criteria provided, single submitter clinical testing This variant, c.95_100dupGCGCCG, results in the insertion of 2 amino acids to the BRAF protein (p.Gly32_Ala33dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with BRAF-related disease. ClinVar contains an entry for this variant (Variation ID: 41448). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acids is currently unknown. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000484992 SCV001482160 likely benign not specified 2021-02-08 criteria provided, single submitter clinical testing Variant summary: BRAF c.95_100dupGCGCCG (p.Gly32_Ala33dup) results in an in-frame duplication that is predicted to duplicate two amino acids into the encoded protein. The variant allele was found at a frequency of 0.00017 in 157184 control chromosomes (gnomAD and publication data). The observed variant frequency is approximately 37 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRAF causing Cardiofaciocutaneous Syndrome phenotype (4.7e-06), strongly suggesting that the variant is benign. c.95_100dupGCGCCG has been reported in the literature in individuals affected with non-small cell lung cancer and hypertrophic cardiomyopathy as well as in one healthy individual (Shen_2019, Lin_2019, Micheu_2020). These reports do not provide unequivocal conclusions about association of the variant with Cardiofaciocutaneous Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV001261041 SCV001438442 likely benign Noonan syndrome no assertion criteria provided clinical testing

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