ClinVar Miner

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

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Total submissions: 23
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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 2020-11-22 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 This alteration is classified as likely 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.
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 RCV000113323 SCV000383700 likely benign Breast-ovarian cancer, familial 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000305604 SCV000383701 likely benign Fanconi anemia, complementation group D1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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
Color Health, Inc 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
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000113323 SCV000744458 likely benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000113323 SCV000745677 likely benign Breast-ovarian cancer, familial 2 2017-05-21 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 RCV001282472 SCV000883519 benign none provided 2019-12-13 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
Mendelics RCV000113323 SCV001139092 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000679173 SCV001148985 likely benign not provided 2018-05-01 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353832 SCV000591911 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Ser1528Ser variant was identified in 25 of 1248 proband chromosomes (frequency: 0.04) from Spanish families with breast and ovarian cancer, and was not identified in 200 control chromosomes from healthy individuals (Diez 2003).The variant was also identified in dbSNP (ID: rs80359788) “With Uncertain significance allele”, with a minor allele frequency of 0.001 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), LOVD, the ClinVar database (with one “uncertain significance” classification from BIC, benign submission from Invitae and benign submission from GeneDX), the BIC database (2X with unknown clinical importance), and UMD (21X as a neutral variant). In addition, Myriad classifies this as a polymorphism (personal communication). In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (c.3331_3334delCAAG (p.Gln1111AsnfsX5) of BRCA1gene and c.4926_4935del (p.Asn1642LysfsX25) of BRCA2 gene), increasing the likelihood that the p.Ser1528Ser variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 2 of 2000 chromosomes (frequency: 0.001), Exome Variant Server project in 3 of 4406 African American alleles, increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin. The p.Ser1528Ser variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site.The p.Ser1528Ser variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs(SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
True Health Diagnostics RCV000163135 SCV000805243 likely benign Hereditary cancer-predisposing syndrome 2018-06-18 no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000679173 SCV001952133 likely benign not provided no assertion criteria provided clinical testing

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