Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000164451 | SCV000215093 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-04-03 | criteria provided, single submitter | clinical testing | The p.Y408D variant (also known as c.1222T>G), located in coding exon 4 of the PALB2 gene, results from a T to G substitution at nucleotide position 1222. The tyrosine at codon 408 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This alteration was observed with an allele frequency of 0.00028 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.0000 in 11,241 female controls of Japanese ancestry. In addition, it was observed with an allele frequency of 0.0000 in 53 unselected male breast cancer patients and was observed with an allele frequency of 0.0001 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Color Diagnostics, |
RCV000164451 | SCV000906859 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-08-07 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001362967 | SCV001559033 | uncertain significance | Familial cancer of breast | 2024-01-07 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 408 of the PALB2 protein (p.Tyr408Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 185091). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PALB2 protein function with a positive predictive value of 80%. 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. |
| Leiden Open Variation Database | RCV001030205 | SCV001193074 | uncertain significance | not provided | 2018-10-10 | no assertion criteria provided | curation | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. |