ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1078C>G (p.Pro360Ala) (rs587782057)

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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 RCV000130533 SCV000185402 uncertain significance Hereditary cancer-predisposing syndrome 2013-11-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000588217 SCV000210261 uncertain significance not provided 2018-09-21 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1078C>G at the cDNA level, p.Pro360Ala (P360A) at the protein level, and results in the change of a Proline to an Alanine (CCA>GCA). Using alternate nomenclature, this variant would be defined as BRCA2 1306C>G. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Pro360Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Pro360Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588217 SCV000694505 uncertain significance not provided 2016-12-27 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.1078C>G (p.Pro360Ala) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 1/120608 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000689505 SCV000817159 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-09 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 360 of the BRCA2 protein (p.Pro360Ala). The proline residue is weakly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs587782057, 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: 141850). 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 alanine 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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