ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7958T>C (p.Leu2653Pro) (rs80359022)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000505706 SCV000210452 pathogenic not provided 2017-10-19 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.7958T>C at the cDNA level, p.Leu2653Pro (L2653P) at the protein level, and results in the change of a Leucine to a Proline (CTT>CCT). Using alternate nomenclature, this variant would be defined as BRCA2 8186T>C. Functional studies have determined that BRCA2 Leu2653Pro produces a defective protein with respect to homology-directed DNA repair, ability to rescue lethality in BRCA2-deficient mouse embryonic stem cells, sensitivity to DNA-damaging agents, and genomic integrity (Biswas 2012, Guidugli 2013). Furthermore, this variant was strongly predicted by Lindor et al. (2012) to be deleterious based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious variants. BRCA2 Leu2653Pro was not observed in large population cohorts (Lek 2016). Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Leu2653Pro occurs at a position that is conserved across species and is located in the DNA binding domain and the DSS1 contacting residue (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the current evidence, we consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113844 SCV000327771 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000575206 SCV000665947 likely pathogenic Hereditary cancer-predisposing syndrome 2019-01-07 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);Other strong data supporting pathogenic classification;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting pathogenic classification
Color RCV000575206 SCV000683922 pathogenic Hereditary cancer-predisposing syndrome 2017-03-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505706 SCV000889143 pathogenic not provided 2019-01-03 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data are high quality (0/282708 chr). Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Moderate co-segregation with disease, and data include affected and unaffected individuals from multiple families.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770732 SCV000902213 likely pathogenic Breast and/or ovarian cancer 2017-08-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113844 SCV000147227 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000113844 SCV000297558 likely pathogenic Breast-ovarian cancer, familial 2 2012-08-15 no assertion criteria provided clinical testing

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