ClinVar Genomic variation as it relates to human health

Detected in circulating white blood cells of at least two individuals with late-onset ovarian cancer, but may represent genomic instability or clonal hematopoiesis (PMID: 24262437); Nonsense variant predicted to result in protein truncation as the last 54 amino acids are lost; This variant is associated with the following publications: (PMID: 23907125, 30388424, 30216591, 30850729, 29752822, 35496359, 28343630, 24262437, 36555431, 37183572, 34312540, 33057194, 35982159, 37378944)

Variant summary: PPM1D c.1654C>T (p.Arg552X) results in a premature termination codon located in the last exon that is suggesting escape from nonsense-mediated mRNA decay (NMD), and is predicted to cause a truncation of the encoded protein sequence (Jansen_2017). The variant allele was found at a frequency of 1.1e-05 in 282676 control chromosomes in the gnomAD database, although it must be noted that 2 of the 3 reported samples failed the quality control process, therefore these occurrences might not represent true germline variants. c.1654C>T has been reported in the literature in an individual affected with a syndromic intellectual disability disorder (i.e. Jansen-de Vries Syndrome), however as parental DNA was not available, the mode of inheritance in this case couldn't be established (Jansen_2017). This variant was also found in peripheral white blood cell derived DNA samples from individuals affected with ovarian- and breast cancer (e.g. Akbari_2014, Amuzu_2018, Li_2018), however these studies did not exclude the possibility of potential somatic mosaicism. Somatic occurrence with a low variant fraction (VF) was found in a peripheral blood sample from a healthy individual (Weber-Lassalle_2018). This study also reported that truncating variants in the PPM1D gene occurred with generally low VFs in blood-derived DNA from several ovarian cancer patients undergoing chemotherapy. In accordance with these findings, a recent functional study demonstrated that cell lines carrying PPM1D mutations (including a truncating mutation in the last exon) can expand to outcompete normal cells after exposure to cytotoxic DNA damaging agents (Hsu_2018). Two publications reported experimental evidence evaluating the impact of the variant on protein function, and demonstrated reduced protein levels (Dudgeon_2013) and increased phosphatase activity (Hsu_2018); these data do not allow convincing conclusions about the variant effect. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

The PPM1D c.1654C>T variant is predicted to result in premature protein termination (p.Arg552*). This variant has been reported in a study in which de novo variants in the terminal and penultimate exons were associated with mild to severe intellectual disability and/or developmental delay, although parents were unavailable for testing to determine inheritance in the patient with this variant (Jansen et al. 2017. PubMed ID: 28343630). This variant has also been reported as occurring in DNA from peripheral blood of at least two individuals with late-onset ovarian cancer (Akbari et al. 2014. PubMed ID: 24262437), as a mosaic variant in cases and controls in studies of patients with breast or ovarian cancer (Table S4, Machiela et al. 2019. PubMed ID: 30850729; Weber-Lassalle et al. 2018. PubMed ID: 30216591), as a germline variant in a patient with high hereditary risk for breast cancer (Table S4, Li et al. 2018. PubMed ID: 29752822), and in a patient with diffuse cerebellar glioma (Nomura et al. 2017. PubMed ID: 28852847). Functional studies demonstrated this variant led to reduced protein levels (Dudgeon et al. 2013. PubMed ID: 23907125) and increased phosphatase activity (Figure S2, Hsu et al. 2018. PubMed ID: 30388424). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD, although NGS read frequency is skewed suggestive of somatic mosaicism in some individuals (http://gnomad.broadinstitute.org/variant/17-58740749-C-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Variant of uncertain significance (VUS) classification is justified because of lack of data of PPM1D genetic variants playing role in lung cancer. A heterozygous nonsense variation in exon 6 of the PPM1D gene (chr17:g.60663388C>T; Depth: 148x) that results in a stop codon and premature truncation of the protein at codon 552 (p.Arg552Ter; ENST00000305921.8) was detected. The variant has been previously reported for ovarian and breast cancers and has been classified as likely pathogenic, but due to the lack of data on lung cancers we have classified it as VUS. The minor allelic frequency (MAF) is 0.003% as per the GnomAD database. This variant has been reported in ovarian and breast cancer (Akbari_2014, Amuzu_2018, Li_2018). But reports on the role of this genetic variant is less understood. However an association study shows the likely possible role of p.Arg552Ter in lung cancer