ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4685A>C (p.Gln1562Pro) (rs544688816)

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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 RCV000218490 SCV000273273 uncertain significance Hereditary cancer-predisposing syndrome 2015-01-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000218490 SCV000906087 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000483116 SCV000564781 uncertain significance not provided 2015-02-19 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4685A>C at the cDNA level, p.Gln1562Pro (Q1562P) at the protein level, and results in the change of a Glutamine to a Proline (CAA>CCA). Using alternate nomenclature, this variant would be defined as BRCA2 4913A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gln1562Pro was not observed at a significant allele frequency in 1000 Genomes. Since Glutamine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Gln1562Pro occurs at a position that is moderately conserved across species and is located in the RAD51 binding motif (Roy 2012). 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 Gln1562Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000697106 SCV000825700 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-05-22 criteria provided, single submitter clinical testing This sequence change replaces glutamine with proline at codon 1562 of the BRCA2 protein (p.Gln1562Pro). The glutamine residue is weakly conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is present in population databases (rs544688816, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 229904). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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