ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4185+2_4185+22delinsA (rs273900724)

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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) RCV000031155 SCV001161635 pathogenic Breast-ovarian cancer, familial 1 2019-06-18 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 = 0.999914
Ambry Genetics RCV000215384 SCV000272963 pathogenic Hereditary cancer-predisposing syndrome 2019-02-06 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Other strong data supporting pathogenic classification
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000031155 SCV000296299 pathogenic Breast-ovarian cancer, familial 1 2015-02-24 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031155 SCV000325878 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Invitae RCV000496532 SCV000635953 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-19 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 11 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with breast cancer (PMID: 12938098). This variant is also known as IVS12+2insAdel21 in the literature. ClinVar contains an entry for this variant (Variation ID: 37574). Experimental studies have shown that this splice site change results in the retention of intron 11 in the processed mRNA product, causing a frameshift and utilization of a premature stop codon (PMID: 12938098). Intron 11 is also known as intron 12 in the literature. Based on a multifactorial likelihood algorithm using genetic data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331). For these reasons, this variant has been classified as Pathogenic.
Color RCV000215384 SCV000688473 pathogenic Hereditary cancer-predisposing syndrome 2020-02-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000496532 SCV001361836 pathogenic Hereditary breast and ovarian cancer syndrome 2019-07-08 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4185+2_4185+22delinsA 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: Five predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Meyer_2003). The variant was absent in 250278 control chromosomes (gnomAD). c.4185+2_4185+22delinsA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Meyer_2003, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submission (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031155 SCV000053755 pathogenic Breast-ovarian cancer, familial 1 2012-06-07 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031155 SCV000145014 pathogenic Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496532 SCV000587381 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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