ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.10121C>T (p.Thr3374Ile) (rs56309455)

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Total submissions: 13
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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) RCV000077246 SCV001161576 benign Breast-ovarian cancer, familial 2 2019-06-18 reviewed by expert panel curation Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00237 (African), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Invitae RCV000167783 SCV000071731 benign Hereditary breast and ovarian cancer syndrome 2020-11-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131153 SCV000186095 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Subpopulation frequency in support of benign classification
GeneDx RCV001719789 SCV000210698 likely benign not provided 2021-04-01 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24728327, 23415752, 12442275, 18284688, 25348012, 15001988, 15889636, 27621404, 27527004, 28526081, 30254663, 31131967)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120375 SCV000334634 likely benign not specified 2015-09-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131153 SCV000683395 likely benign Hereditary cancer-predisposing syndrome 2015-03-11 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285089 SCV001471441 likely benign none provided 2020-06-23 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642574 SCV001852874 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
ITMI RCV000120375 SCV000084527 not provided not specified 2013-09-19 no assertion provided reference population
Sharing Clinical Reports Project (SCRP) RCV000077246 SCV000109043 likely benign Breast-ovarian cancer, familial 2 2007-12-03 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077246 SCV000145757 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000077246 SCV000189908 benign Breast-ovarian cancer, familial 2 2014-07-24 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000077246 SCV000592313 likely benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The BRCA2 p.Thr3374Ile variant was identified in 3 of 2236 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast and ovarian cancer and was present in 12 of 1498 control chromosomes (frequency: 0.08) from healthy individuals (Ruiz-Flores 2002, Calderon-Garciduneas 2005, Bodian 2014, Zuntini 2018). The variant was identified in dbSNP (rs56309455) as “with other allele, ClinVar (classified as likely benign by GeneDx, Color, SCRP and 2 other submitters, benign by Invitae, Ambry Genetics and Pathway Genomics and uncertain significance by BIC), LOVD 3.0 (observed 3x) and UMD-LSDB (observed 7x). The variant was identified in control databases in 79 of 282,668 chromosomes (1 homozygous) at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 59 of 24,960 chromosomes (freq: 0.002), Other in 4 of 7214 chromosomes (freq: 0.0006), Latino in 15 of 35,410 chromosomes (freq: 0.0004), European in 1 of 129,038 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish and South Asian populations. The variant was identified in our laboratory and UMD-LSDB in individuals with co-occurring pathogenic BRIP1 (c.1195G>T, p.Glu399*) and BRCA1 (c.3008_3009delTT p.Phe1003*) variants. The p.Thr3374 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not 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.

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