ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.81-11del

gnomAD frequency: 0.00004  dbSNP: rs273902788
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen RCV000031280 SCV004101440 benign Breast-ovarian cancer, familial, susceptibility to, 1 2023-10-12 reviewed by expert panel curation 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).
Invitae RCV001080354 SCV000259218 benign Hereditary breast ovarian cancer syndrome 2024-01-25 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000579775 SCV000683361 benign Hereditary cancer-predisposing syndrome 2017-01-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001818196 SCV000699305 benign not specified 2022-11-28 criteria provided, single submitter clinical testing 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.
Mendelics RCV000031280 SCV001140649 likely benign Breast-ovarian cancer, familial, susceptibility to, 1 2019-05-28 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 RCV001090205 SCV001245503 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 criteria provided, single submitter clinical testing
GeneDx RCV000587423 SCV001887701 benign not provided 2015-03-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 27616075, 17924331, 21990134)
Genetic Services Laboratory, University of Chicago RCV001818196 SCV002070092 likely benign not specified 2020-01-24 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000579775 SCV002537908 likely benign Hereditary cancer-predisposing syndrome 2021-01-23 criteria provided, single submitter curation
Ambry Genetics RCV000579775 SCV002678243 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001818196 SCV002774146 benign not specified 2021-09-01 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000031280 SCV004819703 benign Breast-ovarian cancer, familial, susceptibility to, 1 2023-12-14 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031280 SCV000053885 likely benign Breast-ovarian cancer, familial, susceptibility to, 1 2007-11-16 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031280 SCV000144216 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001358173 SCV001553844 likely benign Malignant tumor of breast no assertion criteria provided clinical testing 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.

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