PALB2 NM_024675.4:c.3132A>T, Gln1044His

The p.Q1044H variant (also known as c.3132A>T), located in coding exon 11 of the PALB2 gene, results from an A to T substitution at nucleotide position 3132. The glutamine at codon 1044 is replaced by histidine, an amino acid with highly similar properties. This alteration was identified in 0/7840 cases of breast cancer and 1/7928 controls from Malaysia and Singapore (Ng PS et al. J Med Genet, 2021 Apr;:). 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.

This missense variant replaces glutamine with histidine at codon 1044 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. A function study has reported that this variant does not impact PALB2 function in a homology-directed DNA repair assay (PMID: 31636395). This variant has been detected in two breast cancer case-control studies in 0/60466 cases and 1/53461 unaffected individuals (PMID: 33471991Leiden Open Variation Database DB-ID PALB2_010782) and 0/7840 cases and 1/7928 controls (PMID: 33811135). This variant also has been reported in 1 individual age 70 years or older without cancer in the FLOSSIES database (https://whi.color.com/variant/16-23625394-T-A). This variant has been identified in 22/1612054 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.