ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7051G>C (p.Ala2351Pro) (rs80358930)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195376 SCV000073142 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 2351 of the BRCA2 protein (p.Ala2351Pro). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and proline. This variant is present in population databases (rs80358930, ExAC 0.001%). This variant has been reported in individuals affected with clinical features of hereditary breast and ovarian cancer syndrome (PMID: 28111427). ClinVar contains an entry for this variant (Variation ID: 52257). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV000132200 SCV000187282 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Insufficient or conflicting evidence
GeneDx RCV000590253 SCV000210415 uncertain significance not provided 2017-04-11 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7051G>C at the cDNA level, p.Ala2351Pro (A2351P) at the protein level, and results in the change of an Alanine to a Proline (GCA>CCA). Using alternate nomenclature, this variant would be defined as BRCA2 7279G>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala2351Pro was not observed at a significant frequency in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Alanine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Ala2351Pro occurs at a position that is not conserved and is located in the FANCD2 binding domain (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 Ala2351Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000113697 SCV000488872 uncertain significance Breast-ovarian cancer, familial 2 2016-07-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590253 SCV000695030 uncertain significance not provided 2016-10-24 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7051G>C (p.Ala2351Pro) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/120970 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). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590253 SCV000889123 uncertain significance not provided 2019-05-10 criteria provided, single submitter clinical testing
Color RCV000132200 SCV000906929 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-14 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113697 SCV000147008 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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