ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2566T>C (p.Tyr856His) (rs80356892)

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Total submissions: 20
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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) RCV000111891 SCV000244323 benign Breast-ovarian cancer, familial 1 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 = 0.00018. Also class 1 based on frequency >1% in an outbred sampleset. Frequency 0.01399 (Asian), derived from 1000 genomes (2012-04-30).
Invitae RCV000047882 SCV000075895 benign Hereditary breast and ovarian cancer syndrome 2020-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000123907 SCV000167281 benign not specified 2014-02-10 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 RCV000162587 SCV000213003 benign Hereditary cancer-predisposing syndrome 2014-11-18 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 RCV000111891 SCV000220480 benign Breast-ovarian cancer, familial 1 2014-07-04 criteria provided, single submitter literature only
Michigan Medical Genetics Laboratories,University of Michigan RCV000111891 SCV000267703 benign Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000111891 SCV000403064 benign Breast-ovarian cancer, familial 1 2018-03-06 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Baylor Genetics RCV000456795 SCV000540988 benign Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000111891 SCV000575708 likely benign Breast-ovarian cancer, familial 1 2015-08-28 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000123907 SCV000586886 benign not specified 2017-04-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000123907 SCV000602658 benign not specified 2018-07-16 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000162587 SCV000679703 likely benign Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162587 SCV000683048 benign Hereditary cancer-predisposing syndrome 2015-03-31 criteria provided, single submitter clinical testing
GeneKor MSA RCV000123907 SCV000693608 benign not specified 2017-11-01 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000111891 SCV000744653 benign Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769715 SCV000901135 benign Breast and/or ovarian cancer 2016-03-03 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111891 SCV000144476 uncertain significance Breast-ovarian cancer, familial 1 2006-07-19 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000111891 SCV000189333 benign Breast-ovarian cancer, familial 1 2011-02-25 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148383 SCV000190081 likely benign Breast neoplasm 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353898 SCV000591395 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Tyr856His variant was identified in 21 of 4034 proband chromosomes (frequency: 0.0.005) from Korean, Malaysian and Japanese individuals or families with breast cancer, and was not identified in 718 control chromosomes from healthy individuals (Han S-H 2006, Thirthagiri 2008, Toh 2008, Mitsuru Emi 1998). The variant was (also) identified by our laboratory in 6 individuals with breast or ovarian cancer, with one individual in the presence of a second BRCA1 pathogenic variant (c.81-?_134+?del). In a functional complementation assay using BRCA1-deficient mouse embryonic stem cells, the variant was found to be neutral (Bouwman 2013). Promkan et al (2013), showed that BRCA1 (Tyr856His)-transfected mutant cells interfered with the function of wildtype BRCA1 by increased cellular proliferation, which may have implications for chemotherapeutic treatment. Multiple in silico prediction and evolutionary models show that the variant is neutral (Abkevich 2004, Burk-Herrick 2005, Lindor 2012, Spearman 2008, Tavtigian 2006) The variant was identified in dbSNP (ID: rs80356892) “With Likely benign allele”, Clinvitae database (classification benign/likely benign), Fanconi Anemia Mutation Database (LOVD), LOVD-IARC database, ARUP Laboratories BRCA Mutations Database (classification not pathogenic), the ClinVar database (classification benign, reviewed by an expert panel, submitters: ENIGMA, Ambry Genetics, Counsyl, Invitae, Gene Dx, Sharing Clinical Report Project (SCRP) (derived from Myriad reports), classification likely benign by CSER, and uncertain significance by BIC), GeneInsight COGR database (unclassified, “by a clinical laboratory(ies)”), the BIC database (18X with unknown clinical importance, pending classification), and UMD (6X with a “neutral” classification). The variant was also identified in 1000 Genomes Project in 15 of 5000 chromosomes (frequency: 0.003), HAPMAP-EAS in 14 of 1008 chromosomes (frequency: 0.0139), HAPMAP-AMR in 1 of 694 chromosomes (frequency: 0.0014), NHLBI GO Exome Sequencing Project (ESP) in 1 of 4406 African American alleles (frequency: 0.0002), and the the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 184 of 121322 chromosomes (frequency: 0.0015) (or 180 individuals (3 homozygous) from a population of East Asian individuals, 3 South Asian and 1 Latino individual. In addition, this variant is classified as a polymorphism by Myriad (personal communication). The p.Tyr856 residue is not conserved in mammals and lower organisms, and the variant amino acid His is present in African clawed frog, increasing the likelihood that this variant does not have clinical significance. Four out of five 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. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

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