ClinVar Genomic variation as it relates to human health

This missense variant replaces valine with alanine 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 detected in an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010785). This variant has not been identified 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.3107T>C (p.Val1036Ala) results in a non-conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251404 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3107T>C has been reported in the literature in individuals affected with breast cancer (example Ng_2021). These report(s) 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1036 of the PALB2 protein (p.Val1036Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 33811135). ClinVar contains an entry for this variant (Variation ID: 490081). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.

The p.V1036A variant (also known as c.3107T>C), located in coding exon 10 of the PALB2 gene, results from a T to C substitution at nucleotide position 3107. The valine at codon 1036 is replaced by alanine, an amino acid with similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Dorling et al. N Engl J Med. 2021 02;384:428-439; Ng PS et al. J Med Genet, 2022 May;59:481-491). 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.