ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7055C>T (p.Pro2352Leu) (rs80358934)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045131 SCV000073144 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 2352 of the BRCA2 protein (p.Pro2352Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs80358934, ExAC 0.001%). This variant has been reported in individuals with breast cancer in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 52258). 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: "Deleterious"; 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 RCV000222667 SCV000274877 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
Counsyl RCV000113699 SCV000488167 uncertain significance Breast-ovarian cancer, familial 2 2016-01-13 criteria provided, single submitter clinical testing
GeneDx RCV000588738 SCV000566369 uncertain significance not provided 2015-04-24 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7055C>T at the cDNA level, p.Pro2352Leu (P2352L) at the protein level, and results in the change of a Proline to a Leucine (CCT>CTT). Using alternate nomenclature, this variant would be defined as BRCA2 7283C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Pro2352Leu was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Pro2352Leu occurs at a position that is not conserved across species and is located within the region of interaction with FANCD2 (Uniprot). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA2 Pro2352Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000222667 SCV000683847 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588738 SCV000695032 uncertain significance not provided 2016-07-15 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7055C>T (p.Pro2352Leu) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). Pro2352 is not located in a known functional domain of Breast cancer type 2 susceptibility protein. This variant was found in 1/121010 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; 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.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000113699 SCV000744509 uncertain significance Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113699 SCV000147011 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000113699 SCV000733292 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing

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