ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5378A>C (p.Lys1793Thr) (rs730881446)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159853 SCV000209897 uncertain significance not provided 2014-04-22 criteria provided, single submitter clinical testing A variant of uncertain significance displaying apparent mosaicism was detected, meaning the variant was detected in some, but not all, cells. This variant is denoted BRCA1 c.5378A>C at the cDNA level, p.Lys1793Thr (K1793T) at the protein level, and results in the change of a Lysine to a Threonine (AAG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Lys1793Thr was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Lysine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Lys1793Thr occurs at a position that is well conserved across species and is located in the BRCT 2 domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Lys1793Thr is pathogenic or benign. We consider it to be a variant of uncertain significance. This variant appears to be mosaic, as the variant allele was present but underrepresented in comparison to the normal allele. This result was confirmed using alternate, non-overlapping primers, making it unlikely that this result is due to preferential amplification of the normal allele. Therefore, this variant is interpreted to be present in some, but not all, cells in this peripheral blood specimen. Neither Sanger nor Next Generation sequencing is a quantitative test; thus, it is not possible to determine more precisely the level of mosaicism in this specimen. Moreover, the level of mosaicism may be different in other tissues. As somatic mosaicism generally results from a post-zygotic event, parents and siblings are not likely at risk to carry this mosaic variant. Germline mosaicism and transmission to the offspring of this patient, however, cannot be excluded. Mosaicism for BRCA mutations has been reported in at least two individuals, including a BRCA1 mosaic deletion in an individual with early-onset bilateral breast cancer and a BRCA2 mosaic frameshift variant in an individual with Fanconi Anemia due to a FANCB mutation (Alter 2007, Delon 2013).

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