ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5332+4A>G (rs80358166)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131936 SCV000186992 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx RCV000160005 SCV000210216 uncertain significance not provided 2014-07-16 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5332+4A>G or IVS20+4A>G and consists of an A>G nucleotide substitution at the +4 position of intron 20 of the BRCA1 gene. Multiple in silico models predict this variant to weaken the nearby natural donor site, and to possibly cause abnormal gene splicing. This variant, also known as IVS21+4A>G using alternate nomenclature, has been observed in an individual with a history suggestive of Hereditary Breast and Ovarian Cancer syndrome (Lecarpentier 2012) BRCA1 c.5332+4A>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The adenine (A) nucleotide that is altered is well conserved across species. Based on currently available information, it is unclear whether BRCA1 c.5332+4A>G is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000131936 SCV000908982 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-14 criteria provided, single submitter clinical testing
Invitae RCV000807389 SCV000947437 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change falls in intron 20 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 present in population databases (rs80358166, ExAC 0.03%). This variant has been observed in a family with clinical features of hereditary breast and ovarian cancer syndrome (PMID: 125827). This variant is also known as IVS21+4A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 125827). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112618 SCV000145460 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing

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