ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9728C>T (p.Pro3243Leu) (rs80359241)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167844 SCV000073905 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-07 criteria provided, single submitter clinical testing
GeneDx RCV000587179 SCV000210692 likely benign not provided 2018-04-04 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 21218378)
Ambry Genetics RCV000166251 SCV000217031 likely benign Hereditary cancer-predisposing syndrome 2018-06-20 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587179 SCV000296526 uncertain significance not provided 2020-04-22 criteria provided, single submitter clinical testing
Counsyl RCV000031845 SCV000487774 uncertain significance Breast-ovarian cancer, familial 2 2015-11-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000045892 SCV000602772 uncertain significance not specified 2016-08-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045892 SCV000695266 likely benign not specified 2021-07-18 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9728C>T (p.Pro3243Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251118 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9728C>T has been reported in the literature as a VUS in settings of individuals affected with and/or undergoing multigene panel testing for Hereditary Breast And Ovarian Cancer (example, Carney_2010, Shao_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=4; VUS, n=3). At-least one submitter has re-classified this variant from a VUS to likely benign since its previous evaluation by our laboratory. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the emerging peer consensus and the lack of any evidence supporting an actionable outcome as outlined above, the variant was re-classified as likely benign.
Color Health, Inc RCV000166251 SCV000902988 likely benign Hereditary cancer-predisposing syndrome 2017-04-03 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031845 SCV000054453 benign Breast-ovarian cancer, familial 2 2010-09-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031845 SCV000147704 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353590 SCV000592305 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The p.Pro3243Leu variant was not identified in the literature, nor was it identified in NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, COSMIC, GeneInsight VariantWire, BIC or UMD. The variant was identified in the dbSNP database (ID#:rs80359241), but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined; the Exome Aggregation Consortium (ExAC) (released Oct 20th, 2014) in 2 of 121336 chromosomes (frequency: 0.0000) from a population of East Asian (2/8642 individuals), and not in European (Non-Finnish or Finnish), Other, African, Latino, South Asian individuals; and, it was identified in ClinVar (classified as a likely benign variant by the Sharing Clinical Reports Project, derived from Myriad reports; classified as uncertain significance by BIC; and classification not provided by Invitae). The Breast Cancer IARC database notes a weak/null probability the variant creates a de novo splice donor at nt 9728 and a low probability of creating a de novo splice acceptor at nt 9736. The p.Pro3243 residue is not conserved in mammals and lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The c.9728C>T variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. This variant is classified as a variant of unknown significance.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735633 SCV000863771 uncertain significance Breast and/or ovarian cancer 2014-11-21 no assertion criteria provided clinical testing

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