PALB2 NM_024675.3:c.3089C>T, Thr1030Ile

The p.T1030I variant (also known as c.3089C>T), located in coding exon 10 of the PALB2 gene, results from a C to T substitution at nucleotide position 3089. The threonine at codon 1030 is replaced by isoleucine, an amino acid with similar properties. This variant was identified in a series of >800 familial breast cancer cases in Germany (Hellebrand H et al, Hum. Mutat. 2011 Jun; 32(6):E2176-88). Functional analyses of the p.T1030I allele have shown reductions in protein stability and binding efficiency to RAD51C and RAD1, but intact BRCA2 interaction (Park JY et al, Oncogene 2014 Oct; 33(40):4803-12). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1030 of the PALB2 protein (p.Thr1030Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 21618343). ClinVar contains an entry for this variant (Variation ID: 232977). 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 expected to disrupt PALB2 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PALB2 function (PMID: 24141787, 31586400, 33964450). 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.