ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.316+5G>A (rs81002840)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077294 SCV001156532 pathogenic Breast-ovarian cancer, familial 2 2018-04-01 reviewed by expert panel curation Almost complete (94%) skipping of exon 3 (r.68_316del) in a minigene splicing assay. Molecular consequence is the same as other variants designated as pathogenic as determined by multifactorial likelihood analysis (PMID: 29707112). Specifically, pathogenic consequence of the in-frame transcript without exon 3 has been shown in another family with a deletion of this exon, by co-segregation analysis with LR >1300:1 in favour of pathogenicity (PMID: 29707112).
Invitae RCV000044130 SCV000072143 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-23 criteria provided, single submitter clinical testing This sequence change falls in intron 3 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with breast and ovarian cancer (PMID: 21769658,29470806, 26207792, 21120943). In addition, this variant segregates with breast and prostate cancer in one family (PMID: 29707112). ClinVar contains an entry for this variant (Variation ID: 51409). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this sequence change causes skipping of exon 3 of the BRCA2 mRNA (PMID: 121769658, 29707112). Skipping of exon 3 results in in-frame deletion of 83 amino acid residues from the BRCA2 protein partially including the PALB2 binding domain, which is important for DNA repair activity of the BRCA2 protein (PMID: 19609323, 19369211, 22678057, 16793542). A different variant affecting this nucleotide (c.316+5G>C) has been determined to be pathogenic (PMID: 18424508, 22505045, 29707112, 21120943, 21939546, 24549055). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000216220 SCV000273756 pathogenic Hereditary cancer-predisposing syndrome 2019-11-14 criteria provided, single submitter clinical testing The c.316+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 2 in the BRCA2 gene. This mutation has been identified in kindreds with hereditary breast and ovarian cancer (Muller D et al. BMC Med. Genet. 2011; 12:121) as well as in one family with members diagnosed with various types of cancers, including early onset breast cancer, prostate cancer, abdominal cancer, and basal cell carcinoma (Thomassen M et al. Breast Cancer Res. Treat. 2012 Apr;132(3):1009-23). Additionally, functional analysis has demonstrated that this alteration leads to a skipping of coding exon 2, a region with a high degree of evolutionary conservation and importance for protein function (Thomassen M et al. Breast Cancer Res.Treat. 2012 Apr; 132(3):1009-23). Of note, this alteration is also designated as IVS3+5G>A in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000486888 SCV000568446 likely pathogenic not provided 2016-08-15 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.316+5G>A or IVS3+5G>A and consists of a G>A nucleotide substitution at the +5 position of intron 3 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 544+5G>A. This variant was observed in several individuals with a personal and family history of breast and/or ovarian cancer (Thomassen 2012, Decker 2013). Multiple in silico models predict, and RT-PCR analysis confirm, that this variant causes and in-frame deletion of exon 3 (Thomassen 2012, Decker 2013). Although an alternate isoform of BRCA2 lacking exon 3 has been described in multiple tissues, the level of this transcript is significantly more abundant in those harboring BRCA2 544+5G>A, and other similar variants that also result in exon 3 skipping (Muller 2011, Thomassen 2012). BRCA2 c.316+5G>A was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The guanine (G) nucleotide that is altered is conserved across species. Based on the currently available evidence, we consider BRCA2 c.316+5G>A to be a likely pathogenic variant.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486888 SCV000600541 likely pathogenic not provided 2017-06-02 criteria provided, single submitter clinical testing
Mendelics RCV000044130 SCV000838728 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000216220 SCV000906876 pathogenic Hereditary cancer-predisposing syndrome 2017-04-04 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077294 SCV000109091 pathogenic Breast-ovarian cancer, familial 2 2012-09-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077294 SCV000146565 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735537 SCV000863675 pathogenic Breast and/or ovarian cancer 2013-04-04 no assertion criteria provided clinical testing

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