ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9634G>C (p.Gly3212Arg) (rs55775473)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001079612 SCV000073883 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000679198 SCV000108649 likely benign not provided 2021-05-17 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 15744044, 11030418, 12491487, 25556971, 24728327, 28814288, 30362333, 18284688, 23231788, 19491284, 22034289)
Ambry Genetics RCV000131495 SCV000186484 benign Hereditary cancer-predisposing syndrome 2018-09-11 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Michigan Medical Genetics Laboratories,University of Michigan RCV000031840 SCV000196028 likely benign Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
Counsyl RCV000031840 SCV000220768 likely benign Breast-ovarian cancer, familial 2 2014-10-03 criteria provided, single submitter literature only
PreventionGenetics,PreventionGenetics RCV000679198 SCV000805797 likely benign not provided 2017-07-11 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120372 SCV000859229 likely benign not specified 2018-01-16 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000679198 SCV000885102 likely benign not provided 2017-07-17 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131495 SCV000902738 benign Hereditary cancer-predisposing syndrome 2016-05-24 criteria provided, single submitter clinical testing
Mendelics RCV000031840 SCV001139270 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031840 SCV000054448 uncertain significance Breast-ovarian cancer, familial 2 2008-03-24 no assertion criteria provided clinical testing
ITMI RCV000120372 SCV000084524 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000031840 SCV000147681 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 RCV001353941 SCV000592298 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2, p.Gly3212Arg variant was identified in 12 of 1272 proband chromosomes (frequency: 0.009) from individuals or families with breast cancer (Fackenthal 2012, Trujillano 2015). The variant was also identified in dbSNP (ID: rs55775473) as “other”, Clinvitae database (classified as benign by Invitae; classified as likely benign by ClinVar), the ClinVar database (classified as benign by Invitae; classified as likely benign by GeneDx, Ambry Genetics, Counsyl, MMGLUM; classified as uncertain significance by SCRP, BIC), the BIC database (10x with unknown clinical importance), UMD (36x with an “unclassified variant” classification) and Fanconi Anemia Mutation Database (LOVD). In UMD the variant was identified with co-occurring pathogenic BRCA2 variants (c.2612C>A, p.Ser871X and c.1310_1313delAAGA, p.Lys437IlefsX22), increasing the likelihood that the p.Gly3212Arg variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 12 of 5000 chromosomes (frequency: 0.0024), the NHLBI GO Exome Sequencing Project in 19 of 4406 African American alleles, the Exome Aggregation Consortium database (August 8, 2016) in 62 of 121384 chromosomes (freq. 0.0005) in the following populations: African in 60 of 10406 chromosomes (freq. 0.006) and Latino in 2 of 11568 chromosomes (freq. 0.0002), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Gly3212 residue is conserved across mammals and other organisms, and one out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; loss of splicing site at a non-splice site consensus sequence. However, this information is not predictive enough to assume pathogenicity. 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.

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