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

gnomAD frequency: 0.00004  dbSNP: rs273902788

Total submissions: 14

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: 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
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.