Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000218288 | SCV000273227 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-01-12 | criteria provided, single submitter | clinical testing | The p.Q206* pathogenic mutation (also known as c.616C>T or 735C>T) located in coding exon 8 of the BRCA1 gene, results from a C to T substitution at nucleotide position 616. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This mutation has been reported in an Eastern Chinese breast cancer patient with strong family history of the disease (Hu et al., Hum Mutat. 2003; 22(1):104). Alterations that result in premature protein truncation are typically deleterious in nature. However, because this alteration occurs in one of the two exons that are absent in an in-frame, partially functional, naturally occurring isoform (Δ7_8 which is known in the literature as BRCA1 Δ9_10), it has an uncertain impact on pathogenicity (Colombo M et al. Hum. Mol. Genet. 2014 Jul;23:3666-80; Whiley PJ et al. Clin. Chem. 2014 Feb;60:341-52). As such, the clinical significance of this alteration remains unclear. |
Invitae | RCV001360643 | SCV001556570 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2021-01-22 | criteria provided, single submitter | clinical testing | This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12815604, 30702160). This variant is also known as c.735C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 55647). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the BRCA1 gene (p.Gln206*). It is expected to result in an absent or disrupted protein product. However, this sequence variant may be functionally rescued by a naturally occurring isoform of BRCA1 lacking exons 8 and 9. 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. Loss-of-function variants in BRCA1 are expected to be pathogenic (PMID: 20104584). However, detailed characterization of the splicing patterns of the BRCA1 gene has identified an in-frame BRCA1 isoform lacking exons 8 and 9 (also known as exons 9 and 10). This Δ8-9 isoform is highly expressed in normal breast tissue and blood of unaffected individuals, suggesting it may not be deleterious. In addition, this naturally occurring isoform results in the in-frame deletion of 41 amino acid residues that do not overlap a known clinically important functional domain of the BRCA1 protein, and therefore may retain functional activity (PMID: 24569164, 30832263). Taken together, these observations suggest that the Δ8-9 isoform has the potential to maintain BRCA1 protein function and rescue loss-of-function variants within these exons (PMID: 24569164, 27008870). Additional clinical and/or functional data is required to establish the pathogenicity of these variants. |
Laboratory for Genotyping Development, |
RCV003162424 | SCV002758209 | pathogenic | Gastric cancer | 2021-07-01 | no assertion criteria provided | research |