ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9257-1G>C (rs81002889)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131040 SCV000185970 pathogenic Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation
Breast Cancer Information Core (BIC) (BRCA2) RCV000083156 SCV000147590 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000083156 SCV000328089 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000212288 SCV000210500 pathogenic not provided 2016-05-26 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.9257-1 G>C or IVS24-1 G>C and consists of a G>C nucleotide substitution at the -1 position of intron 24 of the BRCA2 gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant, also called BRCA2 c.9485-1G>C, has been reported in an individual with familial breast/ovarian cancer (Laitman 2011).
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000083156 SCV000839924 pathogenic Breast-ovarian cancer, familial 2 2017-07-31 criteria provided, single submitter clinical testing This variant abolishes the canonical splicing site at the accepting end of intron 24 of BRCA2. It is predicted to cause abnormal splicing of BRCA transcript. Experimental data indeed showed this variant cause abberent mRNA (PMID 21394826). It has been reported in multiple patients with familial breast/ovarian cancers (PMID: 20960228, 25452441). This variant has been classified as pathogenic.
Invitae RCV000045767 SCV000073780 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-17 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 24. It is expected to disrupt mRNA splicing. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 20960228, 21120943, 25452441). This variant has also been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). It is also known as IVS24-1G>C and 9485-1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 52793). Multifactorial likelihood analyses based on genetic evidence such as family history, co-segregation with disease, and co-occurrence with pathogenic variants predict that this variant is likely deleterious (PMID: 17924331, 21394826, 21990134). Experimental studies have shown that this variant alters mRNA splicing, either by skipping exon 25, resulting in an out-of-frame transcript, or by utilizing a cryptic splice site in exon 25 that results in the in-frame deletion of 27 nucleotides (9 amino acids) (PMID: 21394826, 25382762). While the out-of-frame transcript is expected to result in an absent protein product due to nonsense-mediated decay, the effect of the in-frame deletion on protein expression, stability, and function has not been experimentally tested. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212288 SCV000600851 pathogenic not provided 2016-11-21 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083156 SCV000115230 likely pathogenic Breast-ovarian cancer, familial 2 2011-09-14 no assertion criteria provided clinical testing

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