Submissions for variant NM_000059.4(BRCA2):c.4143AGA[1] (p.Glu1382del)

dbSNP: rs80359432

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031464	SCV001161614	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 1.46E-06
Invitae	RCV000225744	SCV000072373	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129284	SCV000184045	likely benign	Hereditary cancer-predisposing syndrome	2019-03-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV001284422	SCV000210603	likely benign	not provided	2018-05-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24094589, 26543556, 19941162, 15695382, 17624602, 26183948, 11044354, 24323938)
Counsyl	RCV000031464	SCV000489218	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-11	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044360	SCV000538485	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Clinvar: 3 labs classify as LB, 1 as VUS; ExAC: 2/6606 European chromosomes
Color Diagnostics, LLC DBA Color Health	RCV000129284	SCV000688853	benign	Hereditary cancer-predisposing syndrome	2015-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044360	SCV000694746	likely benign	not specified	2023-01-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4146_4148delAGA (p.Glu1382del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as benign (class 1) in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). The variant allele was found at a frequency of 7.3e-05 in 246448 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (7.3e-05 vs 0.00075), allowing no conclusion about variant significance. c.4146_4148delAGA has been reported in the literature in individuals affected with Breast and Ovarian Cancer (example, Wu_2005, Bosdet_2013, Monnerat_2007, Dodova_2015, Pharoah_2000). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported in the UMD database and at our laboratory (UMD database, BRCA1 c.4162_4163delCA, p.Gln1388GlufsX2; Our laboratory, BRIP1 c.2010dupT , p.Glu671Ter), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Wu_2005). The most pronounced variant effect results in conflicting evidence between HDR activity (supportive of loss), nuclear localization (normal), sensitivity to mitomycin C (MMC, supportive of loss), and centrosome number (normal) with the authors concluding that functional effects alone should not be taken as definite proof for pathogenicity as there is lacking information about cosegregation and limited patient reports. Multiple 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. Multiple submitters reported the variant with conflicting assessments (Benign, n=3 to include the expert panel; likely benign, n=3; VUS, n=5). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above supported by an emerging majority consensus among peers and the expert panel, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000044360	SCV001157438	uncertain significance	not specified	2019-05-02	criteria provided, single submitter	clinical testing	The BRCA2 c.4146_4148delAGA; p.Glu1382del variant (rs80359432) is reported in the literature in several individuals affected with breast cancer (Dodova 2015, Monnerat 2007), although a pathogenic variant in TP53 was also found in one affected individual (Monnerat 2007). This variant is found in the general population with an overall allele frequency of 0.007% (20/276904 alleles) in the Genome Aggregation Database, and it is reported in ClinVar (Variation ID: 37883). This variant deletes a single glutamate residue, leaving the rest of the protein in-frame. In functional assays, this variant exhibits decreased ability to promote cell survival and homology-directed repair, though it does not induce centrosome amplification (Wu 2005). However, due to limited clinical data, the significance of the p.Glu1382del variant is uncertain at this time. References: Dodova RI et al. Spectrum and frequencies of BRCA1/2 mutations in Bulgarian high risk breast cancer patients. BMC Cancer. 2015 Jul 17;15:523. Monnerat C et al. BRCA1, BRCA2, TP53, and CDKN2A germline mutations in patients with breast cancer and cutaneous melanoma. Fam Cancer. 2007;6(4):453-61. Wu K et al. Functional evaluation and cancer risk assessment of BRCA2 unclassified variants. Cancer Res. 2005 Jan 15;65(2):417-26.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284422	SCV001470213	uncertain significance	not provided	2023-06-02	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 26183948 (2015), 17624602 (2007), and 11044354 (2000)). Functional studies have reported that this variant may have deleterious effects on BRCA2 protein function, however further studies are needed to determine the global effect of this variant on BRCA2 protein activity (PMID: 15695382 (2005)). The frequency of this variant in the general population, 0.000078 (10/127472 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798042	SCV002043032	uncertain significance	Breast and/or ovarian cancer	2020-05-14	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000225744	SCV002504849	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000044360	SCV004243029	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944851	SCV004766160	uncertain significance	BRCA2-related condition	2023-12-09	criteria provided, single submitter	clinical testing	The BRCA2 c.4146_4148delAGA variant is predicted to result in an in-frame deletion (p.Glu1382del). This variant has been reported to impair homology directed repair and exhibit hypersensitivity to mitomycin C, but did not alter centrosome amplification using in vitro assays (Guidugli L et al 2013. PubMed ID: 24323938). The c.4146_4148del variant has been reported a limited number of cases of breast cancer (Monnerat et al. 2007. PubMed ID: 17624602; Dodova RI et al 2015. PubMed ID: 26183948). This variant is reported in 0.024% of alleles in individuals of European (Finnish) descent in gnomAD and has been interpreted as uncertain, likely benign, and benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37883/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Sharing Clinical Reports Project (SCRP)	RCV000031464	SCV000054069	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2008-09-24	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031464	SCV000146383	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	RCV001353706	SCV000591892	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Glu1382del variant is an in-frame deletion resulting in the removal of a glutamic acid (Glu) residue at position 1382. This variant has been identified in the literature and was identified in the LOVD database, in the BIC database 5X as a variant of unknown clinical importance, and is listed in the dbSNP database (ID#: rs80359432) “with non-pathogenic allele”, however no frequency information was provided. The variant was also identified in the UMD database (1x as an "unknown variant") where it was reported as co-occurring with another pathogenic variant (BRCA1 c.4162_4163delCA (p.Gln1388GlufsX2)), increasing the likelihood that the p.Glu1382del variant does not have clinical significance. This residue is not conserved in mammals, with a different amino acid, glycine (Gly), present in opossum at this position. One functional study suggested that the variant specifically alters Rad51 binding by BRCA2, resulting in loss of DNA repair activity (Wu 2005). However, the results of other functional assays in this study, including evaluation of nuclear localization and centrosome number, were similar to wild type BRCA2 which suggests that the variant may not confer a conformational change on BRCA2 that leads to inactivation of all BRCA2 functions (Wu 2005). 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).
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000044360	SCV001980273	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031464	SCV004243624	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing