ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5193+3_5193+15del (rs273901752)

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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 RCV000131828 SCV000186883 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-28 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000200277 SCV000254995 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-03-13 criteria provided, single submitter clinical testing This sequence change falls in intron 18 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 in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 142603). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, 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 RCV000779913 SCV000570010 uncertain significance not specified 2016-04-15 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5193+3_5193+15del13 or IVS18+3_IVS18+15del13 and consists of a deletion of 13 nucleotides at the +3 to +15 position in intron 18 of the BRCA1 gene. The normal sequence with the bases that are deleted in braces is AGgt[del13]taca, where the capital letters are exonic and lowercase are intronic. Multiple in silico models predict this variant to destroy the nearby natural donor site, and to possibly cause abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. BRCA1 c.5193+3_5193+15del13 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. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Based on the currently available information, we consider BRCA1 c.5193+3_5193+15del13 to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000779913 SCV000916824 uncertain significance not specified 2018-12-03 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5193+3_5193+15del13 alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. One predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 245844 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5193+3_5193+15del13 in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112552 SCV000145381 pathogenic Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing

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