Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000484915 | SCV000567123 | uncertain significance | not provided | 2015-07-10 | criteria provided, single submitter | clinical testing | This variant is denoted PALB2 c.1600T>G at the cDNA level, p.Ser534Ala (S534A) at the protein level, and results in the change of a Serine to an Alanine (TCT>GCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PALB2 Ser534Ala 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. Since Serine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Ser534Ala occurs at a position that is not conserved and is located in the DNA-binding domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether PALB2 Ser534Ala is pathogenic or benign. We consider it to be a variant of uncertain significance. |
| Labcorp Genetics |
RCV000689372 | SCV000817020 | uncertain significance | Familial cancer of breast | 2024-10-10 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 534 of the PALB2 protein (p.Ser534Ala). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 419370). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31636395). 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. |
| Ambry Genetics | RCV001012375 | SCV001172814 | likely benign | Hereditary cancer-predisposing syndrome | 2024-04-22 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Color Diagnostics, |
RCV001012375 | SCV004357915 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-10-12 | criteria provided, single submitter | clinical testing | This missense variant replaces serine with alanine at codon 534 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant does not disrupt homology directed repair activity of PALB2 (PMID: 31636395). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251484 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Integrative Tumor Epidemiology Branch, |
RCV002266967 | SCV002549701 | uncertain significance | Chordoma | 2021-03-22 | no assertion criteria provided | research | No effect on HRR activity |