ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4484+6A>C (rs879255297)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000239327 SCV000296488 uncertain significance Breast-ovarian cancer, familial 1 2016-06-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780981 SCV000918704 uncertain significance not specified 2017-10-09 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4484+6A>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 2/245932 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color RCV001183807 SCV001349638 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-03 criteria provided, single submitter clinical testing
Invitae RCV001205069 SCV001376305 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-10-08 criteria provided, single submitter clinical testing This sequence change falls in intron 13 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 conditions. ClinVar contains an entry for this variant (Variation ID: 252403). 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.

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