ClinVar Genomic variation as it relates to human health

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1036 of the PALB2 protein (p.Val1036Leu). This variant is present in population databases (rs756906403, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 26283626, 28779002). ClinVar contains an entry for this variant (Variation ID: 188131). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 valine with leucine at codon 1036 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 26283626, 28779002), ovarian cancer (PMID: 32546565) and in a breast cancer case-control meta-analysis in 4/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010334). This variant has been identified in 2/251404 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.V1036L variant (also known as c.3106G>C), located in coding exon 10 of the PALB2 gene, results from a G to C substitution at nucleotide position 3106. The valine at codon 1036 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in a breast cancer patient who had previously tested negative for mutations in the BRCA1/2 genes (Thompson ER et al. Breast Cancer Res. 2015 Aug 19;17:111). This alteration has been reported in 1/13087 breast cancer cases and in 1/5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). 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.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26283626, 32546565, Gordon2000[Book], 19609323, 20871615, 33471991)

Variant summary: PALB2 c.3106G>C (p.Val1036Leu) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of 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 8e-06 in 251404 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3106G>C has been reported in the literature in individuals affected with breast cancer and ovarian cancer (Thompson_2015, Decker_2017, Song_2021), but it has also been reported in controls (Decker_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Melissa DeRycke.