ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.213-14C>G (rs1060502337)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457568 SCV000549321 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-06-13 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual undergoing genetic counseling and BRCA1/BRCA2 testing (PMID: 30832263). ClinVar contains an entry for this variant (Variation ID: 409321). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 30832263). 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.
Mendelics RCV000457568 SCV000839309 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000989912 SCV001140641 uncertain significance Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193717 SCV001362762 uncertain significance not specified 2019-07-15 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.213-14C>G alters a non-conserved 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: three predict the variant creates a 3' cryptic acceptor site, while one predicts the variant weakens the canonical 3' acceptor site. An in vitro functional study found that the variant results in a partial splicing effect, generating an abnormal product with an intronic retention of 59 bases that causes a frameshift with a premature stop codon (p.Arg71SerfsX11) in about 13% of the BRCA1 transcripts (Gelli_2019). The variant was absent in 250918 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.213-14C>G has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Gelli_2019). This report however does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. In addition, co-occurrence with another pathogenic BRCA1 variant has been reported (BRCA1 c.220C>T, p.Gln74X), providing supporting evidence for a benign role. Two ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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