ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4143AGA[1] (p.Glu1382del) (rs80359432)

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Total submissions: 13
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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 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 and ovarian cancer syndrome 2020-11-17 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 Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other data supporting benign classification
GeneDx RCV000044360 SCV000210603 likely benign not specified 2017-10-05 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl RCV000031464 SCV000489218 uncertain significance Breast-ovarian cancer, familial 2 2016-09-11 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare 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 Health, Inc 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 uncertain significance not specified 2019-04-22 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 a Glu amino acid from the encoded protein. The variant allele was found at a frequency of 7.2e-05 in 277856 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (7.2e-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 (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. Co-occurrences with other pathogenic variant(s) have been reported in the UMD database (ascertained in 2017, BRCA1 c.4162_4163delCA, p.Gln1388GlufsX2), providing supporting evidence for a benign role. Functional studies reported by Wu_2005 support a pathogenic effect, although the same authors conclude that the functional effects alone should not be taken as definite proof for pathogenicity as there is lacking information about cosegregation and limited patient reports. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant three times as uncertain significance and three times as likely benign/benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
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 2020-01-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031464 SCV000054069 likely benign Breast-ovarian cancer, familial 2 2008-09-24 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031464 SCV000146383 uncertain significance Breast-ovarian cancer, familial 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).

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