Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong
The NM_007294.4(BRCA1):c.81-11del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,611,344 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as 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]
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-43115789-TA-T is Benign according to our data. Variant chr17-43115789-TA-T is described in ClinVar as [Benign]. Clinvar id is 37699.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43115789-TA-T is described in Lovd as [Benign].
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:4
Benign, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Dec 14, 2023
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Likely benign, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Nov 16, 2007
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Benign, reviewed by expert panel
curation
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen
Oct 12, 2023
The c.81-11del variant is an intronic variant occurring in intron 2 of the BRCA1 gene. This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This BRCA1 intronic variant is outside of the native donor and acceptor 1,2 splice sites, and SpliceAI predictor score of 0.00 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). This is an intronic variant, and mRNA experimental analysis indicates no impact on splicing (PMID: 21735045), considered strong evidence against pathogenicity (BP7_Strong (RNA)). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.00131 (based on Co-occurrence LR=0.0406; Family History LR=0.0321), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; (PMID: 17924331)). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP4, BP7_Strong (RNA), BP5_Very strong). -
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Feb 20, 2004
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Likely benign, criteria provided, single submitter
clinical testing
Mendelics
May 28, 2019
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not specified Benign:3
Likely benign, criteria provided, single submitter
clinical testing
Genetic Services Laboratory, University of Chicago
Jan 24, 2020
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Benign, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Sep 01, 2021
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Benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Nov 28, 2022
Variant summary: BRCA1 c.81-11delT 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. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes the canonical 3' splicing acceptor site. Three predict the variant no significant impact on splicing. An in vitro assay using RNA from the individual(s) carrying this variant shows that the variant had no effect on splicing (example, Menendez_2011). The variant allele was found at a frequency of 3.6e-05 in 248152 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.81-11delT has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer without a strong evidence of causality (example, Judkins_2005, Easton_2007, Menendez_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been reported in the UMD database (BRCA2 c.9117+2T>C), providing supporting evidence for a benign role. Multifactorial probability models also support a neutral outcome (example, Lindor_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter
curation
Sema4, Sema4
Jan 23, 2021
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Benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Jan 03, 2017
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Benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Nov 18, 2014
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Liquid Biopsy and Cancer Interception Group, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research
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not provided Benign:1
Benign, criteria provided, single submitter
clinical testing
GeneDx
Mar 03, 2015
This variant is associated with the following publications: (PMID: 27616075, 17924331, 21990134) -
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided
clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System
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The BRCA1 c.81-11del variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in ClinVar (6x, Benign by ENIGMA, Invitae, Color; Likely benign by Lab Corp and SCRP; Uncertain by BIC), or LOVD 3.0 (3x as benign). The variant was not identified in UMD-LSDB database. The variant was identified in control databases in 11 of 279514 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24716 chromosomes (freq: 0.00008), Latino in 2 of 34920 chromosomes (freq: 0.00006), European (Non-Finnish) in 6 of 127620 chromosomes (freq: 0.00005), South Asian in 1 of 30012 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish, East Asian, and Finish populations. Menendez et al. report an in vitro assay using RNA from lymphocyte cell cultures form a patient carrying this variant displaying that the variant had no effect on splicing (Menendez 2011). In addition Lindor et al. report a probability model that predicts this variant to be benign (Lindor 2012). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Hereditary breast ovarian cancer syndrome Benign:1