ClinVar

Description

This variant is denoted PALB2 c.3089C>T at the cDNA level, p.Thr1030Ile (T1030I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). This variant has been observed in at least one individual with breast cancer and was associated with decreased protein stability and modestly decreased binding with RAD51C and RAD51 compared to wildtype in an in vitro assay (Park 2014). PALB2 Thr1030Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Thr1030Ile occurs at a position that is conserved in mammals and is located within the WD4 domain as well as the regions required for interaction with RAD51, BRCA2, and POLH and for POLH DNA synthesis stimulation (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. However, in general, missense PALB2 variants are not expected to be disease causing (Tischkowitz 2012). Based on currently available evidence, it is unclear whether PALB2 Thr1030Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.