ClinVar Miner

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

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Total submissions: 7
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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 2020-10-12 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 likely benign Hereditary cancer-predisposing syndrome 2019-12-06 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Insufficient or conflicting evidence;Intact protein function observed by in vitro/ex vivo assays
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 Health, Inc RCV000130650 SCV000683892 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-03 criteria provided, single submitter clinical testing This missense variant replaces serine with cysteine at codon 2533 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant has functional DNA repair activity (PMID: 29884841). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 27153395, 27443514). This variant has been identified in 2/250848 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194022 SCV001363255 uncertain significance not specified 2019-08-12 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7598C>G (p.Ser2533Cys) results in a non-conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250848 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.7598C>G, has been reported in the literature in individuals affected with breast and/or ovarian cancer (Tung_2014, Maxwell_2016), and also in an individual affected with endometrial cancer (Ring_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. The variant has been demonstrated in a functional study to have no damaging effect on homology-directed DNA repair (HDR) activity (Hart_2019). Four ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
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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