Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Evidence- |
RCV000113197 | SCV001156535 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2018-04-01 | reviewed by expert panel | curation | Class 5 Pathogenic based on posterior probability = 1 (PMID: 29707112) from multifactorial likelihood analysis, thresholds for IARC Class as per Plon et al. 2008 (PMID: 18951446). This multifactorial calculation includes co-segregation analysis of 13 families with an LR >6.4E+12:1 in favour of pathogenicity. Complete skipping of exon 3 (r.68_316del) in minigene splicing assay (PMID: 29707112). |
Eurofins Ntd Llc |
RCV000724338 | SCV000228766 | pathogenic | not provided | 2014-10-09 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000210519 | SCV000266782 | pathogenic | Hereditary breast ovarian cancer syndrome | 2015-01-16 | criteria provided, single submitter | clinical testing | This sequence change is an Alu element of subtype Ya5-mediated insertion in exon 3 of the BRCA2 mRNA (c.156_157insAluYa5). The exact size of this insertion is unknown. An AluYa5 transposition has been reported in the literature at this sequence position. It is not present in population databases. An AluYa5 insertion at this position has been clearly defined as a breast cancer causative allele. This insertion is a known founder mutation in the Portuguese population (PMID: 20652400, 18363094, 17513806). Experimental studies have shown that this insertion causes alternative splicing of BRCA2, leading to complete skipping of exon 3 (PMID: 18363094). Skipping of exon 3 leads to an in-frame deletion of amino acid residues 23-105 in the BRCA2 protein. This region contains two transcription-activating regions, and is required for BRCA2 phosphorylation (PMID: 10980621). Low-level exon 3 skipping is known to take place in normal cells, and about 5% leaky altered splicing has been reported in wild-type samples (PMID: 20215541, 21939546). However, deletion of exon 3 is pathogenic, and contributes to hereditary breast and ovarian cancer (PMID: 21939546). Although the exact size of this insertion is unknown, an AluYa5-mediated insertion at this position has been reported as a causative mutation. Therefore, this sequence change has been classified as Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000210519 | SCV001442807 | pathogenic | Hereditary breast ovarian cancer syndrome | 2020-10-15 | criteria provided, single submitter | clinical testing | Variant summary: c.156_157ins? denotes the insertion of an undefined sequence of nucleotides in exon 3 of the BRCA2 gene. Insertion of nucleotides at this position is often described in the literature as c.156_157insAlu, indicating the insertion of an Alu element. The variant (determined to be a founder mutation of Portuguese origin) has been reported in the literature in multiple individuals and families affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Teugels_2005, Machado_2007, Davy_2017, Rebbeck_2018) but was absent in 21694 control chromosomes (gnomAD). These data indicate that the variant is very likely to be associated with disease. Multiple studies report experimental evidence demonstrating the variant results in the in-frame skipping of exon 3 (e.g. Teugels_2005, Machado_2007, Davy_2017). Two ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Genetics Program, |
RCV000210519 | SCV002515239 | pathogenic | Hereditary breast ovarian cancer syndrome | 2021-11-01 | criteria provided, single submitter | research | |
Breast Cancer Information Core |
RCV000113197 | SCV000146266 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | no assertion criteria provided | clinical testing | ||
Laboratoire de Biologie et Génétique du Cancer, |
RCV000113197 | SCV000538191 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | no assertion criteria provided | clinical testing |