ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7598C>G (p.Ser2533Cys) (rs80358987)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045255 SCV000073268 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 2533 of the BRCA2 protein (p.Ser2533Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs80358987, ExAC 0.01%) . This variant has been reported in an individual affected with endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 38108). Experimental studies have shown that this missense change does not have a significant effect on the homology directed repair activity of BRCA2 (PMID: 29884841). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000130650 SCV000185535 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000214587 SCV000278875 uncertain significance not provided 2017-08-10 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7598C>G at the cDNA level, p.Ser2533Cys (S2533C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). This variant, also known as BRCA2 7826C>G using alternate nomenclature, has been reported in at least one individual with breast and/or ovarian cancer and one with endometrial cancer (Maxwell 2016, Ring 2016). BRCA2 Ser2533Cys was not observed at a significant frequency in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser2533Cys occurs at a position that is not conserved and is located in the DNA binding domain and region of interaction with FANCD2 (Yang 2002, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Ser2533Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000130650 SCV000683892 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031690 SCV000054297 uncertain significance Breast-ovarian cancer, familial 2 2007-07-19 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031690 SCV000147132 uncertain significance Breast-ovarian cancer, familial 2 1997-11-13 no assertion criteria provided clinical testing

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