ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3682A>G (p.Asn1228Asp) (rs28897722)

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Total submissions: 18
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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) RCV000031433 SCV000244440 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 = 0.00000548
Invitae RCV000044242 SCV000072255 benign Hereditary breast and ovarian cancer syndrome 2020-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000587829 SCV000210595 likely benign not provided 2020-06-10 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 18724707, 27153395, 17924331, 24323938, 26010302, 16847550, 16760289, 21990134, 32444794)
Ambry Genetics RCV000163003 SCV000213491 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 RCV000031433 SCV000220848 likely benign Breast-ovarian cancer, familial 2 2014-10-31 criteria provided, single submitter literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000044242 SCV000296854 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-11-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163003 SCV000683572 likely benign Hereditary cancer-predisposing syndrome 2015-03-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000160221 SCV000694711 benign not specified 2020-10-27 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3682A>G (p.Asn1228Asp) results in a conservative amino acid change located in the BRCA2 repeat of 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 4e-05 in 249496 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4e-05 vs 0.00075), allowing no conclusion about variant significance. c.3682A>G has been reported in the literature in cohorts of individuals with breast cancer (example, Capalbo_2006, DeBrakeleer_2015, Giannini_2006, Romano_2007, Seymour_2008, Maxwell_2016, Ikeda_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multifactorial probability models have reported a neutral outcome for this variant (Lindor_2012). At-least two co-occurrences with another pathogenic variant have been reported in the BIC database (BRCA2 c.6468_6469delTC, p.Ser2156_Gln2157SerIlefs), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function by a high throughput functional screen (Ikegami_2020). These results showed no damaging effect of this variant as measured by tolerance to treatment with PARP inhibitors. Eight clinical diagnostic laboratories and one expert panel (ENIGMA, classification as benign) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=3, likely benign, n=4, VUS, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the absence of conclusive evidence supporting an actionable outcome as outlined above and to reflect the majority consensus classification in the field, the variant was classified as benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000031433 SCV000743288 likely benign Breast-ovarian cancer, familial 2 2017-07-28 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000031433 SCV000744442 benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000587829 SCV000805698 likely benign not provided 2018-01-24 criteria provided, single submitter clinical testing
Mendelics RCV000031433 SCV001139069 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642311 SCV001854774 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) RCV000031433 SCV000054038 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031433 SCV000146277 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 RCV000031433 SCV001553912 likely benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The BRCA2 p.Asn1228Asp variant was identified in a minimum of 1 of 146 proband chromosomes (frequency: 0.007) from Italian individuals or families with breast/ovarian cancers (Giannini 2006). Computational methods assessing the pathogenicity of unclassified missense variants includes a posterior probability model/likelihood ratio model found the variant not to be deleterious (Lindor 2012, Easton 2007, Rajasekaran 2008). The variant was also identified in dbSBP (ID: rs28897722) “With other allele”, ClinVar (classified as benign, reviewed by an expert panel (last assessed 2015); submitters: benign by ENIGMA, Invitae, Ambry Genetics, SCRP (Sharing Clinical Reports Project, derived from Myriad reports); likely benign by GeneDx, Counsyl; uncertain significance by BIC and Div of Genomic Diagnostics, Children's Hospital of Philadelphia), Clinvitae (4x), LOVD 3.0 (4x), UMD-LSDB (7x with classification 1-Neutral), BIC Database (7x, unknown clinical importance, classification pending), and ARUP Laboratories (classified 1-not pathogenic or of no clinical significance). The variant was not identified in Genesight-COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database. The variant was identified in control databases in 11 of 275416 chromosomes at a frequency of 0.00004 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Asn1228 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, 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000160221 SCV001905887 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000160221 SCV001951387 benign not specified no assertion criteria provided clinical testing

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