ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9292T>C (p.Tyr3098His) (rs41293521)

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Total submissions: 21
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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) RCV000031810 SCV000244493 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 = 0.00000349
Invitae RCV001083603 SCV000073795 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000031810 SCV000196025 benign Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000120370 SCV000210686 likely benign not specified 2018-01-10 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.
Ambry Genetics RCV000163017 SCV000213505 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 RCV000031810 SCV000220608 likely benign Breast-ovarian cancer, familial 2 2014-08-20 criteria provided, single submitter literature only
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768642 SCV000324846 likely benign Breast and/or ovarian cancer 2015-10-16 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000120370 SCV000538492 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Has been reported in 2 families with female breast and ovarian cancer (Serova-Sinilnikova 1997). Has been classified as benign by Akbari 2011 (based on Myriad classification criteria), Bodian 2011 (presence in controls), Guidugli 2014 (functional assay), Lindor 2012 (posterior probability model OR). No functional impact in DNA break repair assay (Guidugli 2013). B/LB by SCRP, GeneDx, Ambry, Counsyl, Invitae; VUS by BIC in ClinVar.
Fulgent Genetics,Fulgent Genetics RCV000031810 SCV000575724 uncertain significance Breast-ovarian cancer, familial 2 2015-08-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163017 SCV000684051 likely benign Hereditary cancer-predisposing syndrome 2015-03-11 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000031810 SCV000743364 likely benign Breast-ovarian cancer, familial 2 2015-08-24 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000031810 SCV000744562 benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000755867 SCV000883494 likely benign not provided 2017-06-05 criteria provided, single submitter clinical testing
Mendelics RCV000031810 SCV001139256 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642512 SCV001852844 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) RCV000031810 SCV000054418 benign Breast-ovarian cancer, familial 2 2008-09-05 no assertion criteria provided clinical testing
ITMI RCV000120370 SCV000084522 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000031810 SCV000147602 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 RCV001353962 SCV000592273 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2, p.Tyr3098His variant was identified in 6 of 5110 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian and prostate cancer (Borg 2010, Edwards 2003, Gayther 1999, Serova-Sinilnikova 1997). The variant was also identified in dbSNP (ID: rs41293521) as “other”, Clinvitae database (classified as benign by ClinVar and Invitae; uncertain significance by ClinVar), ARUP Laboratories BRCA Mutations Database (classified as not pathogenic), the ClinVar database (classified as benign by ENIGMA, MMGLUM, Invitae, Ambry Genetics, SCRP; likely benign by CHEO, GeneDx, Consyl; uncertain significance by BIC), GeneInsight COGR database (classified as benign, likely benign or uncertain significance by a clinical laboratories), the BIC database (33x with unknown clinical importance). This variant was identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004), the Exome Aggregation Consortium database (August 8th 2016) in 31 of 117284 chromosomes (freq. 0.0003) in the following populations: Latino in 15 of 11252 chromosomes (freq. 0.001), European in 15 of 93796 chromosomes (freq. 0.0002), African in 1 of 10290 chromosomes (freq. 0.0001), but was not seen in Asian, Finnish and other populations. In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (c.3841C>T (p.Gln1281X), c.1953dup (p.Lys652GlufsX21); c.6405_6409delCTTAA (p.Asn2135LysfsX3)), increasing the likelihood that the p.Tyr3098His variant does not have clinical significance. The variant was also identified by our laboratory in two individuals with breast cancer. The p.Tyr3098 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 addition, several functional studies classified this variant as class 1 (IARC) with probability of being deleterious 1.07×10−5 (Guidugli 2013, Lindor 2012). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000120370 SCV001799499 benign not specified no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000120370 SCV001905869 benign not specified no assertion criteria provided clinical testing

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