ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3454G>A (p.Asp1152Asn) (rs80357175)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081256 SCV000076216 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129496 SCV000184268 likely benign Hereditary cancer-predisposing syndrome 2019-01-03 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
GeneDx RCV000589160 SCV000210147 uncertain significance not provided 2019-04-10 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20104584, 18500671, 15235020, 25948282, 21232165, 26689913, 26580448, 26941049, 21520273, 25682074, 23704879, 15385441)
Department of Pathology and Molecular Medicine,Queen's University RCV000212174 SCV000588045 uncertain significance not specified 2017-04-20 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000212174 SCV000593681 uncertain significance not specified 2016-09-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212174 SCV000600334 uncertain significance not specified 2017-01-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589160 SCV000699034 likely benign not provided 2017-07-28 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3454G>A (p.Asp1152Asn) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index) (BP4). This variant was found in 2/121394 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant has been reported in multiple affected individuals without strong evidence for causality. The HDR assay showed the variant with relative HDR activity of 1.7306 (WT=1; Lu_2015) (ACMG criteria BS3). One individual reported in UMD also carried a likely pathogenic variant in BRCA1 c.4485_4675del/p.Ser1496GlyfsX14, further supporting benign nature of this variant (ACMG criteria BP2). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, and one classified it as benign, all without evidence for independent evaluation. Taken together, and considering the ACMG guidelines, this variant is classified as likely benign until more evidence becomes available.
PreventionGenetics,PreventionGenetics RCV000589160 SCV000806934 uncertain significance not provided 2017-08-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129496 SCV000902880 likely benign Hereditary cancer-predisposing syndrome 2015-04-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000589160 SCV001151331 uncertain significance not provided 2019-03-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000212174 SCV001160216 uncertain significance not specified 2019-01-09 criteria provided, single submitter clinical testing The BRCA1 c.3454G>A; p.Asp1152Asn variant (rs80357175), also known as 3573G>A in traditional nomenclature, is reported in the literature in multiple individuals affected with breast and/or ovarian cancer, as well as one pediatric patient with leukemia (Borg 2010, Kluska 2015, Stegel 2011, Zhang 2015). This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 54890), and is found in the non-Finnish European population with an allele frequency of 0.0085% (11/129,078 alleles) in the Genome Aggregation Database. The aspartic acid at codon 1152 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. In vitro functional analyses demonstrate activity similar to wildtype in a homology-directed repair assay (Lu 2015). Due to limited information, the clinical significance of the p.Asp1152Asn variant is uncertain at this time. References: Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. Kluska A et al. New recurrent BRCA1/2 mutations in Polish patients with familial breast/ovarian cancer detected by next generation sequencing. BMC Med Genomics. 2015 May 7;8:19. Lu C et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 2015 Dec 22;6:10086. Stegel V et al. The occurrence of germline BRCA1 and BRCA2 sequence alterations in Slovenian population. BMC Med Genet. 2011 Jan 14;12:9. Zhang J et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med. 2015 Dec 10;373(24):2336-2346.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196675 SCV001367306 uncertain significance Familial cancer of breast 2019-09-16 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,BP1.
Institute of Human Genetics, University of Leipzig Medical Center RCV000112100 SCV001440658 likely benign Breast-ovarian cancer, familial 1 2019-01-01 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001662095 SCV001878310 likely 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
Breast Cancer Information Core (BIC) (BRCA1) RCV000112100 SCV000144768 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000112100 SCV000297600 benign Breast-ovarian cancer, familial 1 2010-01-14 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353524 SCV000591448 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Asp1152Asn variant was identified in 1 of 1042 proband chromosomes (frequency: 0.001) from Slovenian individuals or families with breast and/or ovarian cancers, and was not identified in 80 control chromosomes from healthy individuals (Stegel 2011). The variant was identified by our laboratory in 2 individuals with breast cancer. The variant was also identified in dbSNP (ID: rrs80357175 “With Uncertain significance allele”. The variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 2 of 121314 chromosomes (frequency: 0.00001649) or 2 of 66712 European (Non-Finnish) alleles and was not found in populations of South Asians, East Asian, African, Latino, European (Finnish) and other individuals. The p.Asp1152Asn variant was identified in the Clinvar database and was classified as a variant of uncertain significance by Ambry Genetics, GeneDx and BIC; Invitae did not provide a classification. The BRCA Share UMD database identified the variant 3X and classified it as unknown; the variant was identified with a co-occurring BRCA1 pathogenic variant (c.4485_4675del, p.Ser1496GlyfsX14), increasing the likelihood that the p.Asp1152Asn variant does not have clinical significance. BIC database identified the variant 3X with unknown clinical importance. The p.Asp1152 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In addition, evolutionary conservation analysis predicts the variant as neutral (Abkevich 2004). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
MVZ Praenatalmedizin und Genetik Nuernberg RCV000112100 SCV000777893 uncertain significance Breast-ovarian cancer, familial 1 2018-05-01 no assertion criteria provided clinical testing This rare variant (gnomAD) was found multiple times in databases and literature with uncertain significance. In silico analyses show contradictory results. Therefore we rate this variant as Variant of unknown significance (VUS). Interestingly we found this variant in a patient who harbored also a pathogenic BRCA2-variant (NM_000059.3|c.5238dupT|het)

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