ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5073A>G (p.Thr1691=) (rs80356853)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112482 SCV000578059 uncertain significance Breast-ovarian cancer, familial 1 2017-12-15 reviewed by expert panel curation Insufficient evidence to determine clinical significance
Invitae RCV000048763 SCV000076776 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-10-26 criteria provided, single submitter clinical testing This sequence change affects codon 1691 of the BRCA1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA1 protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 55374). This variant is also known as c.5192A>G in the literature. Experimental studies in yeast have shown that this missense change results in compromised transcriptional activation activity (PMID: 12496477). In summary, this variant a rare silent change that has been shown to affect protein function in in vitro studies. However, the clinical significance of these results remains unknown. For these reasons, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000212193 SCV000210196 uncertain significance not provided 2014-07-09 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5073A>G at the DNA level. Although the variant is silent at the coding level, preserving a Threonine at codon 1691, multiple in silico models predict this variant to negatively impact the nearby natural splice donor site, and to possibly cause abnormal gene splicing. This variant, also known as BRCA1 c.5192A>G by alternate nomenclature, was shown to exhibit loss of function when studied by a transcription activation assay (Carvalho 2002). BRCA1 c.5073A>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 nucleotide which is altered, an adenine (A) at base 5073, is well conserved across mammals. Based on currently available information, it is unclear whether BRCA1 c.5073A>G is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000570872 SCV000661087 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-28 criteria provided, single submitter clinical testing Insufficient evidence
Breast Cancer Information Core (BIC) (BRCA1) RCV000112482 SCV000145287 uncertain significance Breast-ovarian cancer, familial 1 2002-03-14 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112482 SCV001244018 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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