ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.156_157insAlu

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724338 SCV000228766 pathogenic not provided 2014-10-09 criteria provided, single submitter clinical testing
Invitae RCV000210519 SCV000266782 pathogenic Hereditary breast and 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.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113197 SCV000146266 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing

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