ClinVar Miner

Submissions for variant NM_007299.4(BRCA1):c.1675-1G>A (rs730881495)

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Total submissions: 7
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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) RCV000172806 SCV000282242 pathogenic Breast-ovarian cancer, familial 1 2016-04-03 reviewed by expert panel curation Allele-specific assay on patient-derived mRNA demonstrated that the variant allele produces only predicted non-functional transcripts. Variant allele produces r.4987_5074del transcript (encoding predicted non-functional protein).
GeneDx RCV000159998 SCV000210192 pathogenic not provided 2017-04-05 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4987-1G>A or IVS15-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 15 of the BRCA1 gene. Using alternate nomenclature, this variant would be defined as BRCA1 5106-1G>A, IVS16-1G>A. This 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 has been shown to cause skipping of exon 17 (exon 16 using internal nomenclature) by RT-PCR studies (Colombo 2013). Based on the current evidence, we consider this variant to be pathogenic.
Pathway Genomics RCV000172806 SCV000223752 likely pathogenic Breast-ovarian cancer, familial 1 2014-10-30 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000172806 SCV000326092 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508328 SCV000602673 pathogenic not specified 2016-08-19 criteria provided, single submitter clinical testing
Counsyl RCV000172806 SCV000677759 pathogenic Breast-ovarian cancer, familial 1 2017-03-28 criteria provided, single submitter clinical testing
Invitae RCV000694301 SCV000822739 pathogenic Hereditary breast and ovarian cancer syndrome 2018-06-12 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 15 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 an individual affected with breast cancer (PMID: 26681312) This variant is also known as IVS16-1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 182165). Experimental studies have shown that this missense change disrupts normal mRNA splicing (PMID: 23451180). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.

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