Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BA1
The NM_001374258.1(BRAF):c.2248-5_2248-4insT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 676,340 control chromosomes in the GnomAD database, including 424 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
BRAF (HGNC:1097): (B-Raf proto-oncogene, serine/threonine kinase) This gene encodes a protein belonging to the RAF family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene, most commonly the V600E mutation, are the most frequently identified cancer-causing mutations in melanoma, and have been identified in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of lung. Mutations in this gene are also associated with cardiofaciocutaneous, Noonan, and Costello syndromes, which exhibit overlapping phenotypes. A pseudogene of this gene has been identified on the X chromosome. [provided by RefSeq, Aug 2017]
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 7-140734774-C-CA is Benign according to our data. Variant chr7-140734774-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44820.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=3, not_provided=1}.
BA1
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BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Oct 10, 2019
Variant summary: BRAF c.2128-5dupT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 151920 control chromosomes. However, multiple benign variants have been found in this polyT region. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x benign, 1x VUS). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter
clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Jun 26, 2015
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not provided, no classification provided
clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Mar 13, 2014
2128-5_2128-4insT in intron 17 of BRAF: This variant is not expected to have clinical significance because it shifts but does not alter the splice consensus sequence. -
Benign, no assertion criteria provided
clinical testing
Clinical Genetics, Academic Medical Center
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not provided Benign:2
Likely benign, no assertion criteria provided
clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
-
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Likely benign, no assertion criteria provided
clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
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Noonan syndrome with multiple lentigines Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Jun 14, 2016
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Cardio-facio-cutaneous syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Jun 14, 2016
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Noonan syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Jun 14, 2016
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RASopathy Benign:1
Benign, criteria provided, single submitter
clinical testing
Invitae
Feb 01, 2024
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Noonan syndrome and Noonan-related syndrome Benign:1
Benign, criteria provided, single submitter
clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children