Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000116098 | SCV000150007 | uncertain significance | not provided | 2016-08-05 | criteria provided, single submitter | clinical testing | This variant is denoted PALB2 c.3132A>C at the cDNA level, p.Gln1044His (Q1044H) at the protein level, and results in the change of a Glutamine to a Histidine (CAA>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PALB2 Gln1044His 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 Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution and may affect protein integrity. PALB2 Gln1044His occurs at a position that is highly conserved across species and is located in within a region that interacts with RAD51 and BRCA2 as well as the WD4 repeat region. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PALB2 Gln1044His is pathogenic or benign. We consider it to be a variant of uncertain significance. |
| Ambry Genetics | RCV000454267 | SCV000538166 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-07-15 | criteria provided, single submitter | clinical testing | The p.Q1044H variant (also known as c.3132A>C), located in coding exon 11 of the PALB2 gene, results from an A to C substitution at nucleotide position 3132. The glutamine at codon 1044 is replaced by histidine, an amino acid with highly similar properties. This alteration was found to be functionally normal in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV000635880 | SCV000757305 | uncertain significance | Familial cancer of breast | 2023-12-30 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1044 of the PALB2 protein (p.Gln1044His). This variant is not present in population databases (gnomAD no frequency). 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: 128138). 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 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. |