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

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	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 (ga)	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, LabCorp	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, Instituto Nacional de Cancer	RCV000210519	SCV002515239	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113197	SCV000146266	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Laboratoire de Biologie et Génétique du Cancer, Centre François Baclesse	RCV000113197	SCV000538191	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing