Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000216463 | SCV000277672 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-11-09 | criteria provided, single submitter | clinical testing | The p.D1398Y variant (also known as c.4192G>T and 4311G>T ), located in coding exon 11 of the BRCA1 gene, results from a G to T substitution at nucleotide position 4192. The aspartic acid at codon 1398 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 225000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be benign and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.D1398Y remains unclear. |
| Invitae | RCV001209292 | SCV001380719 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2021-08-18 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid with tyrosine at codon 1398 of the BRCA1 protein (p.Asp1398Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 233320). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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. |