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 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 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 likely benign not specified 2021-07-03 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 expected 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=2 to include the expert panel; likely benign, n=3; VUS, n=4). 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 re-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 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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