ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7879A>T (p.Ile2627Phe) (rs80359014)

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Total submissions: 14
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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) RCV000077415 SCV000244476 pathogenic 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 5 based on posterior probability = 1
Invitae RCV000045337 SCV000073350 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 2627 of the BRCA2 protein (p.Ile2627Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families with breast and/or ovarian cancer (PMID: 10699917, 20104584, 21232165, 20383589, 25452441, 29335924), as well as in an individual affected with prostate cancer (PMID: 29368341). It is also known as 8107A>T in the literature. ClinVar contains an entry for this variant (Variation ID: 52430). This variant is located in the DNA-binding domain (DBD) of the BRCA2 protein (PMID: 18451181). Experimental studies have shown that this variant affects BRCA2 homology-directed repair activity, regulation of centrosome amplification, and complementation of the lethality in BRCA2-deficient cells (PMID: 18451181, 23108138, 25146914, 29884841). Multifactorial likelihood analyses based on genetic data using family history, co-segregation, and co-occurrence predict that this variant has a high probability of being deleterious (PMID: 17924331, 18451181, 21990134, 23108138). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000131675 SCV000186711 likely pathogenic Hereditary cancer-predisposing syndrome 2018-02-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Michigan Medical Genetics Laboratories,University of Michigan RCV000077415 SCV000267813 pathogenic Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
GeneDx RCV000218666 SCV000278877 pathogenic not provided 2017-08-22 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7879A>T at the cDNA level, p.Ile2627Phe (I2627F) at the protein level, and results in the change of an Isoleucine to a Phenylalanine (ATC>TTC). Using alternate nomenclature, this variant has been previously published as BRCA2 8107A>T. BRCA2 Ile2627Phe has been observed in multiple breast/ovarian cancer families (Spitzer 2000, Balabas 2010, Stegel 2011, Lee 2014, Meisel 2017), and was strongly predicted by Lindor et al. (2012) to be pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious variants. Functional studies demonstrated that BRCA2 Ile2627Phe displayed both reduced homology directed repair activity and an increase in centriole amplification when compared to wild-type, suggesting a disruption of BRCA2 function (Farrugia 2008, Guidugli 2013). BRCA2 Ile2627Phe was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ile2627Phe occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located within the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, we consider BRCA2 Ile2627Phe to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077415 SCV000296502 likely pathogenic Breast-ovarian cancer, familial 2 2016-05-30 criteria provided, single submitter clinical testing
GeneKor MSA RCV000218666 SCV000296832 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077415 SCV000327756 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000045337 SCV000592155 pathogenic Hereditary breast and ovarian cancer syndrome 2016-07-29 criteria provided, single submitter clinical testing
Color RCV000131675 SCV000683913 pathogenic Hereditary cancer-predisposing syndrome 2016-11-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763326 SCV000894003 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3 2018-10-31 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077415 SCV000109213 pathogenic Breast-ovarian cancer, familial 2 2012-03-11 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077415 SCV000147209 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045337 SCV000587918 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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