ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.593+4A>G (rs80358154)

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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 RCV000217340 SCV000272935 likely benign Hereditary cancer-predisposing syndrome 2019-04-26 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
GeneDx RCV000237043 SCV000292503 uncertain significance not provided 2016-02-22 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.593+4A>G or IVS8+4A>G and consists of an A>G nucleotide substitution at the +4 position of intron 8 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. An in vitro splicing assay found that this variant results in deletion of exon 9; however, there is suggestion that deletion of exon 9 is a natural isoform in some tissues (Whiley 2011). The variant, also published as BRCA1 712+4A>G using alternate nomenclature, was predicted by Lindor et al. (2012) to be neutral based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious mutations. BRCA1 c.593+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 not conserved. Based on currently available information, it is unclear whether BRCA1 c.593+4A>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000217340 SCV001345466 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-16 criteria provided, single submitter clinical testing
Invitae RCV001297373 SCV001486385 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-08-15 criteria provided, single submitter clinical testing This sequence change falls in intron 8 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 reported in an individual affected with breast cancer (PMID: 21394826). ClinVar contains an entry for this variant (Variation ID: 55643). Based on a multifactorial likelihood algorithm using genetic data, this variant has been determined to have a low probability of being pathogenic (PMID: 21394826). 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 may cause abnormal splicing (PMID: 21394826. 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) RCV000112748 SCV000145635 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing

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