PALB2 NM_024675.3:c.109C>A, Arg37Ser

The PALB2 c.109C>A (p.Arg37Ser) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 29522266 (2018), 28194609 (2017)). Functional studies indicate this variant has mild to neutral effect on PALB2 DNA repair activity (PMIDs: 33964450 (2021), 31636395 (2020)). The frequency of this variant in the general population, 0.000016 (4/251456 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

This missense variant replaces arginine with serine at codon 37 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. Two functional studies have reported that this variant does not impact BRCA1 function in homology-directed repair assays (PMID: 31636395, 33964450). This variant has been reported in an individual affected with breast cancer (PMID: 28194609) and a suspected hereditary breast and ovarian cancer family (PMID: 29522266). This variant has been identified in 4/251456 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.

Variant summary: PALB2 c.109C>A (p.Arg37Ser) results in a non-conservative amino acid change located in the coiled coil domain (Boonen_2020) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251456 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.109C>A has been observed in individual(s) affected with ER positive, HER negative breast cancer (Lerner-Ellis_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least two publications report primary experimental evidence evaluating an impact on protein function (Wiltshire_2020, Brnich_2021 and reviewed in Boonen_2020). These results showed no damaging effect of this variant on homology directed repair activity (Wiltshire_2019) and an intermediate assay read out on homology directed repair function (Brnich_2021). The following publications have been ascertained in the context of this evaluation (PMID: 33195396, 33964450, 28194609, 31636395). ClinVar contains an entry for this variant (Variation ID: 185108). Based on the evidence outlined above, the variant was classified as uncertain significance.

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

The p.R37S variant (also known as c.109C>A), located in coding exon 3 of the PALB2 gene, results from a C to A substitution at nucleotide position 109. This variant impacts the first base pair of coding exon 3. The arginine at codon 37 is replaced by serine, an amino acid with dissimilar properties. This alteration was found to be functionally normal in DNA-repair assays (Wiltshire T et al. Genet. Med. 2020 03;22:622-632; Brnich SE et al. J Mol Diagn. 2021 07;23:847-864). 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.