ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8177A>G (p.Tyr2726Cys) (rs80359064)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045442 SCV000073455 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-05 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 2726 of the BRCA2 protein (p.Tyr2726Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 25452441, 27495310). ClinVar contains an entry for this variant (Variation ID: 52520). Experimental studies have shown that this variant affects the homology-directed repair (HDR) activity of the BRCA2 protein in vitro (PMID: 23108138, 29394989). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000130671 SCV000185557 likely pathogenic Hereditary cancer-predisposing syndrome 2019-07-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Deficient protein function in appropriate functional assay(s);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Structural Evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000212271 SCV000210466 uncertain significance not provided 2017-11-06 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8177A>G at the cDNA level, p.Tyr2726Cys (Y2726C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant, also defined as BRCA2 8405A>G using alternate nomenclature, has been observed in at least one individual with breast cancer and another with a family history of breast or ovarian cancer (Couch 2015, Jarhelle 2016) and on functional interrogation demonstrated decreased homology-directed repair activity (Guidugli 2013). BRCA2 Tyr2726Cys was not observed at a significant frequency in large population cohorts (Lek 2016). Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Tyr2726Cys occurs at a position that is conserved across species and is located in the DSS1 contacting residue within the DNA binding domain (Yang 2002). In silico analyses predict that this variant is probably damaging to protein structure and function. Despite some evidence suggesting pathogenicity, there is not currently enough information available to conclude whether BRCA2 Tyr2726Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Department of Medical Genetics, Oslo University Hospital RCV000077430 SCV000605687 likely pathogenic Breast-ovarian cancer, familial 2 2015-08-25 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077430 SCV000109228 uncertain significance Breast-ovarian cancer, familial 2 2012-11-30 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077430 SCV000147292 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Department of Medical Genetics, University Hospital of North Norway RCV000077430 SCV000301453 uncertain significance Breast-ovarian cancer, familial 2 2016-05-01 no assertion criteria provided clinical testing

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