ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4672A>C (p.Ser1558Arg) (rs587782822)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132397 SCV000187489 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000255433 SCV000321462 uncertain significance not provided 2015-09-02 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4672A>C at the cDNA level, p.Ser1558Arg (S1558R) at the protein level, and results in the change of a Serine to an Arginine (AGT>CGT). Using alternate nomenclature, this variant would be defined as BRCA2 4900A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ser1558Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Serine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Ser1558Arg occurs at a position that is not conserved and is located in the RAD51-binding BRC repeat region in the linker between repeat 4 and 5 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Ser1558Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000411787 SCV000489365 uncertain significance Breast-ovarian cancer, familial 2 2016-09-27 criteria provided, single submitter clinical testing
Invitae RCV000542360 SCV000635395 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 1558 of the BRCA2 protein (p.Ser1558Arg). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 142923). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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