Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_007294.4(BRCA1):c.441+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000769 in 1,561,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BP6
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BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-43104104-G-A is Benign according to our data. Variant chr17-43104104-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 215873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43104104-G-A is described in Lovd as [Pathogenic]. Variant chr17-43104104-G-A is described in Lovd as [Benign]. Variant chr17-43104104-G-A is described in Lovd as [Likely_benign].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Sep 23, 2019
Variant summary: BRCA1 c.441+18C>T 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. 2/2 computational tools predict no significant impact on normal splicing, and these predictions were confirmed by an mRNA transcript analysis (Houdayer 2012). The variant allele was found at a frequency of 8.1e-05 in 258156 control chromosomes (gnomAD). This frequency is not higher than the expected maximum for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (8.1e-05 vs 0.001), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.441+18C>T in individuals affected with Hereditary Breast and Ovarian Cancer has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign (1x) / likely benign (3x). Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter
clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Aug 15, 2023
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Benign, criteria provided, single submitter
clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Jul 24, 2018
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Benign, no assertion criteria provided
clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
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Breast-ovarian cancer, familial, susceptibility to, 1 Benign:4
Likely benign, no assertion criteria provided
clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
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Likely benign, criteria provided, single submitter
clinical testing
Mendelics
May 28, 2019
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Likely benign, criteria provided, single submitter
clinical testing
Counsyl
Jul 28, 2016
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Likely benign, criteria provided, single submitter
clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Jul 07, 2023
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not provided Benign:3
Benign, criteria provided, single submitter
clinical testing
GeneDx
Mar 03, 2015
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Likely benign, no assertion criteria provided
clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht
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Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Mar 27, 2017
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Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Jun 23, 2016
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Hereditary breast ovarian cancer syndrome Benign:1