ClinVar Genomic variation as it relates to human health

The p.A1079S variant (also known as c.3235G>T), located in coding exon 12 of the PALB2 gene, results from a G to T substitution at nucleotide position 3235. The alanine at codon 1079 is replaced by serine, an amino acid with similar properties. This alteration was reported in a 7 month old patient presenting with isolated myelomonocytic sarcoma (Beer A et al. Mol Genet Genomic Med 2021 09;9(9):e1746). This alteration was also reported in 1/835 familial breast cancer cases and in 0/662 controls in one study (Damiola F et al. Breast Cancer Res. Treat. 2015 Dec;154:463-71) as well as in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This amino acid position is 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.

BP4, PM2

This missense variant replaces alanine with serine at codon 1079 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, controlled functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 26564480, 28779002) and ovarian cancer (PMID: 32546565). This variant has been observed in an infant with thoracic and intraspinal aleukaemic myeloid sarcoma, as well as in his father unaffected with cancer (PMID: 34382369). In a large breast cancer case-control study, this variant has been observed in 6/60466 cases and 1/53461 unaffected individuals with OR=5.305 (95%CI 0.639 to 44.07) and p-value=0.13 (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010612). 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.

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1079 of the PALB2 protein (p.Ala1079Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or myelosarcoma (PMID: 26564480, 34382369). This missense change has been observed to co-occur in individuals with a different variant in PALB2 that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 182756). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.

Observed in individuals with breast cancer and also in unaffected controls (Damiola et al., 2015; Decker et al., 2017; Dorling et al., 2021); Observed in a child with myeloid sarcoma, and a fibroblast sample from this patient demonstrated increased sensitivity to radiation and DNA damaging agents (Beer et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28779002, 24485656, 19609323, 20871615, 33471991, 26564480, 34382369)

Variant summary: PALB2 c.3235G>T (p.Ala1079Ser) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251472 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3235G>T has been reported in the literature in individuals affected with Breast Cancer (e.g. Damiola_2015, Dorling_2021) and acute myelogenous leukaemia (Beer_2021) without evidence for causality, and also in unaffected controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: all six classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.