ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4584C>T (p.Ser1528=) (rs80359788)

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Total submissions: 20
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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) RCV000113323 SCV000579175 likely benign Breast-ovarian cancer, familial 2 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Invitae RCV000044445 SCV000072458 benign Hereditary breast and ovarian cancer syndrome 2017-12-29 criteria provided, single submitter clinical testing
GeneDx RCV000123973 SCV000167366 benign not specified 2013-12-20 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.
Ambry Genetics RCV000163135 SCV000213649 likely benign Hereditary cancer-predisposing syndrome 2014-08-14 criteria provided, single submitter clinical testing
Counsyl RCV000113323 SCV000220354 benign Breast-ovarian cancer, familial 2 2014-05-27 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000679173 SCV000225160 uncertain significance not provided 2015-05-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000044445 SCV000383700 likely benign Hereditary breast and ovarian cancer syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000305604 SCV000383701 likely benign Fanconi anemia 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000044445 SCV000494386 benign Hereditary breast and ovarian cancer syndrome 2015-12-14 criteria provided, single submitter clinical testing Variant summary: The c.4584C>T variant, a synonymous mutation, lies in the middle of exon 11. This variant involves a non-conserved nucleotide and 5/5 in silico splice-site prediction tools via Alamut predict that the variant does not affect normal splicing. This prediction is consistent with the report from Caux-Moncoutier et al (Caux-Moncoutier et al 2009) in which the authors 'indirectly' show that the variant of interest does not result in allelic imbalance due to nonsense mediated decay of aberrant splice products. The variant was found in the general population at a frequency of 0.02% which does not exceed the maximal expected allele frequency of a pathogenic BRCA2 variant (which is 0.075%). However, the frequency of this variant in the Latino population is just above that of the maximal expected allele frequency (0.78%), which suggests this variant to be a polymorphism found mainly in populations of Latin descent. Indeed, several of the reported HBOC patients/families with the variant were from Spain, and co-occurrence and co-segregation were not reported for these patients, suggesting the true disease-causing mutation was not detected/presented. Furthermore, UMD reports co-occurrence with a possibly deleterious truncating BRCA2 variants c.6079dup (p.Arg2027LysfsX22) and c.4926_4935del (p.Asn1642LysfsX25) and with BRCA1 variant c.3331_3334delCAAG (p.Gln1111AsnfsX5) implicating that the variant of interest is in the benign spectrum. Additionally, publications (Osorio_BRCA2_Clin Genet_1998; Diez_BRCA2_HM_2003) and several clinical diagnostic laboratoris classify variant as Polymorphism/Bening/Likely Bening (without evidence to independently evaluate). Considering all evidence, the variant is classified as benign.
Baylor Genetics RCV000471202 SCV000541070 benign Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000123973 SCV000591911 benign not specified 2014-10-24 criteria provided, single submitter clinical testing
Color RCV000163135 SCV000683633 likely benign Hereditary cancer-predisposing syndrome 2015-04-21 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000113323 SCV000743300 likely benign Breast-ovarian cancer, familial 2 2017-07-28 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000113323 SCV000744458 likely benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679173 SCV000805708 likely benign not provided 2017-06-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000679173 SCV000883519 benign not provided 2018-02-12 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769693 SCV000901108 likely benign Breast and/or ovarian cancer 2016-10-26 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113323 SCV000146452 uncertain significance Breast-ovarian cancer, familial 2 2000-06-12 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000113323 SCV000745677 likely benign Breast-ovarian cancer, familial 2 2017-05-21 no assertion criteria provided clinical testing
True Health Diagnostics RCV000163135 SCV000805243 likely benign Hereditary cancer-predisposing syndrome 2018-06-18 no assertion criteria provided clinical testing

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