ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8917C>T (p.Arg2973Cys) (rs45469092)

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Total submissions: 17
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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) RCV000031776 SCV000244489 benign Breast-ovarian cancer, familial 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000178
Invitae RCV001086936 SCV000073670 benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000163016 SCV000213504 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as 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 RCV000031776 SCV000220285 likely benign Breast-ovarian cancer, familial 2 2014-05-01 criteria provided, single submitter literature only
GeneDx RCV000428227 SCV000512394 benign not specified 2015-09-03 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.
Department of Pathology and Molecular Medicine,Queen's University RCV000428227 SCV000588124 benign not specified 2017-04-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000428227 SCV000602818 benign not specified 2016-11-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000428227 SCV000695191 benign not specified 2021-07-19 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8917C>T (p.Arg2973Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 249368 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8917C>T has been reported in the literature in individuals affected with breast cancer and/or ovarian cancer (Lee_2008, Spearman_2008, Lu_2012, Grant_2015, Ricks-Santi_2017, Solodskikh_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one co-occurrence with another pathogenic variant has been internally reported (BRCA1 c.68_69delAG, p.Glu23fsX17), providing supporting evidence for a benign role. Some functional studies report this variant had no or slight impact on protein function (Farrugia_2008, Guidugli_2017, Mesman_2018). Nine ClinVar submitters (evaluation after 2014) cite the variant as benign (7x) and likely benign (2x). In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be neutral (Easton_2007, Lindor_2012). Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics,PreventionGenetics RCV000034469 SCV000805790 likely benign not provided 2017-08-15 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769706 SCV000901125 likely benign Breast and/or ovarian cancer 2017-09-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163016 SCV000910652 benign Hereditary cancer-predisposing syndrome 2016-01-25 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034469 SCV001133956 benign not provided 2019-04-17 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642494 SCV001852818 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
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034469 SCV000043235 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000031776 SCV000054384 benign Breast-ovarian cancer, familial 2 2009-11-25 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031776 SCV000147487 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 RCV000034469 SCV001553009 likely benign not provided no assertion criteria provided clinical testing The BRCA2 p.Arg2973Cys variant was identified in 5 of 3808 proband chromosomes (frequency: 0.001) from individuals or families with breast or pancreatic cancer and was present in 1 of 1144 control chromosomes (frequency: 0.0009) from healthy individuals (Lee 2008, Spearman 2008, Grant 2015, Ricks-Santi 2017). The variant was identified in dbSNP (rs45469092) as “with uncertain significance allele”, ClinVar (classified as benign by Ambry Genetics, GeneDx, ENIGMA, Color and 3 other submitters; as likely benign by Invitae, Counsyl, Prevention Genetics and 2 other submitters; and as uncertain significance by BIC and NIH), LOVD 3.0 (observed 10x) and UMD-LSDB (observed 1x). The variant was identified in control databases in 7 of 280,740 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 7162 chromosomes (freq: 0.0001) and European in 6 of 127,866 chromosomes (freq: 0.00005); it was not observed in the African, Latino , Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. In vitro expression of the variant demonstrated no effect on homology directed repair activity or induction of centrosome amplification (Farrugia 2008, Guidugli 2013). The variant was reported in ClinVar by another clinical laboratory to have been identified in an individual with a co-occurring pathogenic BRCA1 variant (p.Glu23fs*17), decreasing the likelihood that this variant has clinical significance (Integrated Genetics/Laboratory Corporation of America ClinVar submission dated May 31, 2018). The p.Arg2973 residue is conserved in mammals 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 variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of 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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