ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5074+3A>G (rs80358181)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255098 SCV000322278 likely pathogenic not provided 2018-04-30 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5074+3A>G or IVS16+3A>G and consists of an A>G nucleotide substitution at the +3 position of intron 16 of the BRCA1 gene. Also reported as BRCA1 5193+3A>G or IVS17+3A>G using alternate nomenclature, this variant has been observed in several families with breast and/or ovarian cancer (Menendez 2012, Nakamura 2015, Abdel-Razeq 2018). RNA studies have demonstrated that this variant produces aberrant mRNA transcripts, resulting in skipping of exon 16 or insertion of partial intron 16, both of which are predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (Menendez 2012). Additionally, in silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect. This variant was not observed in large population cohorts (Lek 2016). Based on the currently available information, we consider BRCA1 c.5074+3A>G to be a likely pathogenic variant.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000112483 SCV000743382 pathogenic Breast-ovarian cancer, familial 1 2014-10-08 criteria provided, single submitter clinical testing
Invitae RCV001378309 SCV001575854 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-05-12 criteria provided, single submitter clinical testing This sequence change falls in intron 16 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 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 individuals with breast cancer (PMID: 21735045, 24249303, 29409476). This variant is also known as IVS17+3A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 55375). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing and protein function (PMID: 21735045, 30209399). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112483 SCV000145291 uncertain significance Breast-ovarian cancer, familial 1 1999-12-30 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496317 SCV000587452 uncertain significance not specified 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000112483 SCV000733601 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112483 SCV001242049 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
CZECANCA consortium RCV001271029 SCV001451844 likely pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing

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