ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1744A>C (p.Thr582Pro) (rs80358457)

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Total submissions: 14
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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) RCV000031334 SCV000244425 benign Breast-ovarian cancer, familial 2 2015-08-10 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 = 0.0000224
Invitae RCV001079595 SCV000071882 benign Hereditary breast and ovarian cancer syndrome 2020-12-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162597 SCV000213016 benign Hereditary cancer-predisposing syndrome 2014-11-19 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.
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000031334 SCV000267233 uncertain significance Breast-ovarian cancer, familial 2 2016-03-18 criteria provided, single submitter reference population
GeneDx RCV000758864 SCV000512339 likely benign not provided 2020-11-27 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17924331, 24323938, 21990134, 12624724, 9971877, 19491284, 15117986, 17301269, 26260725, 22771033, 15168169, 18779604, 27124784, 27383479, 26332594, 28782087, 29202657, 28111427, 30415210, 32426482)
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000422713 SCV000586929 benign not specified 2017-04-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162597 SCV000683441 likely benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758864 SCV000887756 benign not provided 2019-02-14 criteria provided, single submitter clinical testing
Mendelics RCV000031334 SCV001139008 benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000422713 SCV001362933 benign not specified 2019-09-23 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1744A>C (p.Thr582Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 250296 control chromosomes, predominantly at a frequency of 0.0032 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1744A>C has been reported in the literature in individuals affected with Breast and Ovarian Cancer. However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with a pathogenic variant has been reported (BRCA1 c.505C>T, p.Gln169Ter), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Mondal_2012). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (4x benign-including one expert panel, 3x likely benign, 1x VUS). Based on the evidence outlined above, the variant was classified as benign.
Research and Development, ARUP Laboratories RCV001642266 SCV001854688 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031334 SCV000053939 benign Breast-ovarian cancer, familial 2 2009-08-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031334 SCV000145923 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 RCV001353982 SCV000591762 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Thr582Pro variant has been identified in 6 out of 1488 proband chromosomes (frequency 0.004) in Korean, Asian American, and North American individuals or families with breast and pancreatic cancers ( Couch 2007, Haffty 2009, Choi 2004, Kurian 2008). In a study elucidating the function of BRCA2 in whole chromosomal instability seen in BRCA2-deficient tumors, the variant disrupted interactions with associated partners involved in maintaining chromosomal stability but has no effect on BRCA2-dependent homologous recombination repair of DNA damage (Mondal 2012). The variant was identified in dbSNP (ID: rs80358457) “With uncertain significance, untested allele”, in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004), and in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 27 of 120326 chromosomes (frequency: 0.0002) (or 27 individuals from a population of East Asians, and none from European (Non-Finnish), Other, African, Latino, South Asian, or European (Finnish) individuals); and was identified by our laboratory in 3 individuals with breast cancer. The variant was also identified in the Clinvitae database (2X, classifications benign and conflicting interpretations), Fanconi Anemia Mutation Database (LOVD), ARUP Laboratories BRCA Mutations Database (classified as not pathogenic/of no clinical significance), the ClinVar database (reviewed by an expert panel and classified as benign; specifically, classified as benign by ENIGMA, Ambry Genetics and Sharing Clinical Reports Project (SCRP) (derived from Myriad reports), classified as uncertain significance by BIC, and unclassified by Invitae), GeneInsight COGR database (unclassified by a clinical laboratory), the BIC database (7X with unknown clinical importance, classification pending), and UMD (unavailable). The p.Thr582 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Other variants were also reported impacting the same site including c.1744A>G, p.Thr582Ala (BIC reported 3 times with unknown clinical significance) and c.1744A>T, p.Thr582Ser (Myriad reported as a polymorphism - personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

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