ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7601C>T (p.Ala2534Val) (rs74047012)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001085066 SCV000073269 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-02 criteria provided, single submitter clinical testing
GeneDx RCV000590175 SCV000210430 likely benign not provided 2020-12-18 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25664426, 23415752, 19043619, 21147080, 11240689, 30254663, 30606148, 10815905)
Counsyl RCV000031691 SCV000220346 likely benign Breast-ovarian cancer, familial 2 2014-05-22 criteria provided, single submitter literature only
Ambry Genetics RCV000220233 SCV000273906 likely benign Hereditary cancer-predisposing syndrome 2018-10-02 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590175 SCV000695084 likely benign not provided 2017-01-19 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7601C>T (p.Ala2534Val) variant, alternatively also known as 7829C>T, involves the alteration of a non-conserved nucleotide and is predicted as benign by 4/5 in silico tools. It is located in proximity to the exon-intron boundary (16 nucleotides away) and is predicted to create a cryptic donor site by 2/5 splice prediction tools. ESE finder predicts that this variant may cause loss of an ESE site. This variant was predicted to have uncertain significance by protein likelihood ratio model (Karchin_2008). However, these predictions have yet to be confirmed by functional studies. This variant was found in 12/120468 control chromosomes from ExAC at a frequency of 0.0000996, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503); however, it could still represent as a rare polymorphism. This variant has been reported in multiple breast and/or ovarian cancer patients in literature and clinical databases without strong evidence for pathogenicity. BIC and UMD each report a sample with this variant that also carries BRCA1 c.5263_5264insC (p.Ser1755?fs), strongly supporting for benign outcome (whether both databases reported the same individual is not known). One large case-control study did not find this variant as a significant risk allele (Haiman_2013). Clinical database/reputable databases in ClinVar have conflicting interpretation of this variant; it has been classified as variant of uncertain significance (3) as well as likely benign (3). Therefore, based on currently available lines of evidence, this variant is classified as "likely benign."
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590175 SCV000889135 likely benign not provided 2019-03-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000220233 SCV000911016 benign Hereditary cancer-predisposing syndrome 2016-02-10 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000590175 SCV001148991 uncertain significance not provided 2019-06-01 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642455 SCV001854938 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
Sharing Clinical Reports Project (SCRP) RCV000031691 SCV000054298 likely benign Breast-ovarian cancer, familial 2 2011-02-04 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031691 SCV000147139 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000590175 SCV000592127 likely benign not provided no assertion criteria provided clinical testing The BRCA2 p.Ala2534Val variant was identified in 3 of 186 proband chromosomes (frequency: 0.0161) from individuals or families with hereditary breast and ovarian cancer (de Juan Jimenez 2010, Stordal 2013). The variant was listed in dbSNP (rs74047012) with a minor allele frequency of 0.001 (1000 Genomes Project), and in the NHLBI Exome Sequencing Project (Exome Variant Server) in 1 of 4406 African American alleles (frequency: 0.0002), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant was also identified in the following databases: ClinVar (6x as likely benign by GeneDx, Counsyl, Ambry Genetics, COGR, Invitae, and SCRP and 1x as uncertain significance by BIC), Clinvitae (4x), Cosmic (found 1x in kidney tumour), LOVD 3.0 (5x), BIC Database (5x, clinical importance unknown, classification pending), and UMD-LSDB (9x as uncertain significance). In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (c.5266dup, p.Gln1756ProfsX74), increasing the likelihood that the p.Ala2534Val variant does not have clinical significance. The variant was classified as “likely benign” by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The variant was not identified in MutDB, ARUP Laboratories, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 25 of 276514 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). It was observed in the African population in 6 of 23976 chromosomes (freq: 0.00025), Latino in 1 of 34394 chromosomes (freq: 0.000029), European (Non-Finnish) in 15 of 126190 chromosomes (freq: 0.000119), and South Asian in 3 of 30740 chromosomes (freq: 0.000098); it was not observed in the “Other”, Ashkenazi Jewish, East Asian, and European (Finnish) populations. The p.Ala2534 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Val impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The 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 difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
True Health Diagnostics RCV000220233 SCV000886675 likely benign Hereditary cancer-predisposing syndrome 2018-09-27 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.