Submissions for variant NM_000059.4(BRCA2):c.3858_3860del (p.Lys1286del)

dbSNP: rs80359406

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200063	SCV000072298	benign	Hereditary breast ovarian cancer syndrome	2025-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131324	SCV000186297	likely benign	Hereditary cancer-predisposing syndrome	2018-09-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000859082	SCV000210598	likely benign	not provided	2021-03-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27741520, 19941162, 9971877, 10717622)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000859082	SCV000600566	likely benign	not provided	2023-01-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000859082	SCV000602823	benign	not provided	2024-10-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131324	SCV000683585	likely benign	Hereditary cancer-predisposing syndrome	2015-09-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044285	SCV000694725	benign	not specified	2024-07-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3858_3860delAAA (p.Lys1286del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 7.4e-05 in 1544206 control chromosomes, predominantly at a frequency of 0.0012 within the African or African-American subpopulation in the gnomAD database (v4). The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075). c.3858_3860delAAA has been reported in the literature in individuals affected with breast and/or ovarian Cancer (e.g. Malone_2000, Fernandes_2016, Eygelaar_2022), but also healthy controls (e.g. Wagner_1999). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9971877, 19941162, 23056405, 10717622, 17826769, 27741520, 26933808, 33643918, 35039564). ClinVar contains an entry for this variant (Variation ID: 37861). Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000031442	SCV001139075	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000859082	SCV001716152	uncertain significance	not provided	2019-11-03	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000200063	SCV002026094	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000044285	SCV002066864	likely benign	not specified	2021-11-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131324	SCV002533827	likely benign	Hereditary cancer-predisposing syndrome	2021-07-12	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV003607205	SCV002580092	benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BS1, BP1_STR
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492311	SCV004240307	uncertain significance	Breast and/or ovarian cancer	2022-08-08	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000031442	SCV004805806	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2024-03-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004803023	SCV004845234	likely benign	BRCA2-related cancer predisposition	2024-09-23	criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV000131324	SCV006060688	benign	Hereditary cancer-predisposing syndrome	2025-02-20	criteria provided, single submitter	clinical testing	BS1, BP1_Strong c.3858_3860del, located in exon 11 of the BRCA2 gene, consists in the deletion of 3 nucleotides, predicted to cause an in-frame deletion of 1 amino acid, p.(Lys1286del). This position is outside a (potentially) clinically important functional domain and, moreover, the SpliceAI algorithm predicts no significant impact on splicing (BP1_strong). The variant allele was found in 23/20944 alleles, with a filter allele frequency of 0.0636% at 99% confidence, within the African population in the gnomAD v2.1.1 database (non-cancer data set) (BS1). To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. In addition, it was also identified in the following databases: BRCA Exchange (Not Yet Reviewed), ClinVar (5x benign, 9x likely benign, 7xuncertain significance) and LOVD (1x benign, 1x likely benign, 2x uncertain significance). Based on the currently available information, c.3858_3860del is classified as a benign variant according to ClinGen-BRCA2 Guidelines version v1.0.0.
Sharing Clinical Reports Project (SCRP)	RCV000031442	SCV000054047	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2009-09-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031442	SCV000146313	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353700	SCV000591879	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Lys1286del variant has been previously reported in the literature (Wagner 1999), and was listed 7X in the BIC database with unknown clinical significance. It is listed in the dbSNP database as coming from a “clinical source” (ID#: rs80359407) however no frequency information was provided. This is an in frame-deletion which removes amino acid, Lys, from the encoded BRCA2 protein at codon 1286, however the impact on the protein function is not known. In summary, the clinical significance of this variant cannot be determined with certainty at this time. Therefore this variant is classified as a variant of unknown significance (VUS).
Molecular Oncology - Human Genetics Lab, University of Sao Paulo	RCV001843463	SCV002103124	uncertain significance	Hepatoblastoma		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004541037	SCV004771533	likely benign	BRCA2-related disorder	2020-08-02	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).