ClinVar Genomic variation as it relates to human health

Variant summary: PALB2 c.1468C>G (p.Pro490Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246212 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1468C>G, has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Tung_2015). This report does not provide an unequivocal conclusion about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Observed in a patient with male breast cancer (Tung et al., 2015); Published functional study demonstrated no impairment of homologous repair function (Brnich et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33964450, 25186627)

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 490 of the PALB2 protein (p.Pro490Ala). 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: 241531). 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: 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.

This missense variant replaces proline with alanine at codon 490 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. A functional study reported that this variant does not impact PALB2 in a homology-directed repair assay (PMID: 33964450). This variant has been reported in an individual affected with male breast cancer (PMID: 25186627) and has been detected in a breast cancer case-control meta-analysis in 0/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_011024). This variant has been identified in 1/251416 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.

The p.P490A variant (also known as c.1468C>G), located in coding exon 4 of the PALB2 gene, results from a C to G substitution at nucleotide position 1468. The proline at codon 490 is replaced by alanine, an amino acid with highly similar properties. This alteration has been identified in an individual undergoing multigene panel testing for hereditary breast and/or ovarian cancer (Tung N et al. Cancer 2015 Jan;121(1):25-33). This amino acid position is not well 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.