ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.476-2A>G

dbSNP: rs81002853
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Total submissions: 13
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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) RCV000031504 SCV000244452 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1
Ambry Genetics RCV000131855 SCV000186910 pathogenic Hereditary cancer-predisposing syndrome 2022-12-16 criteria provided, single submitter clinical testing The c.476-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides before coding exon 5 of the BRCA2 gene. This mutation was found in 4 of 1010 unrelated individuals from high-risk breast and/or ovarian cancer families in the Czech Republic (Machockova E et al. BMC Cancer. 2008 May 20;8:140). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Colombo M et al. PLoS One. 2013;8(2):e57173; Machockova E et al. BMC Cancer. 2008 May 20;8:140). This alteration is unable to complement cell growth in a BRCA2-null mouse embryonic stem cell assay (Mesman RLS et al. Genet Med, 2020 08;22:1355-1365). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031504 SCV000327085 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-10-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506489 SCV000600609 pathogenic not provided 2017-06-01 criteria provided, single submitter clinical testing
Counsyl RCV000031504 SCV000785372 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2017-07-14 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001387341 SCV001587948 pathogenic Hereditary breast ovarian cancer syndrome 2023-09-21 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 18489799, 27062684, 29084914). This variant is also known as IVS5-2A>G. ClinVar contains an entry for this variant (Variation ID: 37923). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21990134). Studies have shown that disruption of this splice site results in skipping of exon 6 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001387341 SCV002819941 pathogenic Hereditary breast ovarian cancer syndrome 2022-12-05 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.476-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. RT-PCR analysis showed the variant to result in two abnormal transcripts, one lacking exon 6 and one lacking exon 5-6, both predicted to result in premature termination codons (Colombo_2013). The variant was absent in 251060 control chromosomes. c.476-2A>G has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (eg. Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity RCV000506489 SCV003812530 pathogenic not provided 2022-12-14 criteria provided, single submitter clinical testing
Baylor Genetics RCV003473180 SCV004210376 pathogenic Familial cancer of breast 2023-03-08 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000506489 SCV004225710 pathogenic not provided 2023-04-20 criteria provided, single submitter clinical testing PP5, PM2, PVS1
Sharing Clinical Reports Project (SCRP) RCV000031504 SCV000054109 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031504 SCV000146941 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2004-02-20 no assertion criteria provided clinical testing
CZECANCA consortium RCV001271039 SCV001451856 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided case-control

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