ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.442-3T>C (rs8176139)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000460631 SCV000549386 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-10 criteria provided, single submitter clinical testing This sequence change falls in intron 6 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 not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 409351). 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.
GeneDx RCV000767158 SCV000572639 uncertain significance not provided 2017-01-02 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.442-3T>C or IVS6-3T>C and consists of a T>C nucleotide substitution at the -3 position of intron 6 of the BRCA1 gene. Using alternate nomenclature, this variant would be defined as BRCA1 561-3T>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 c.442-3T>C was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The thymine (T) nucleotide that is altered is conserved across species. In silico models are inconclusive with respect to splicing, and in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA1 c.442-3T>C is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484818 SCV000605877 uncertain significance not specified 2016-10-13 criteria provided, single submitter clinical testing

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