Submissions for variant NM_003620.4(PPM1D):c.1654C>T (p.Arg552Ter)

gnomAD frequency: 0.00004  dbSNP: rs779070661

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000760458	SCV000890345	likely pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	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)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194426	SCV001363973	likely pathogenic	Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold	2019-09-12	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV002249460	SCV002518896	pathogenic	Familial cancer of breast	2022-05-04	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV001194426	SCV002581889	pathogenic	Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold	2022-09-05	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV001194426	SCV004045823	pathogenic	Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold	2023-03-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003411698	SCV004116397	uncertain significance	PPM1D-related disorder	2023-02-03	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000760458	SCV005804056	uncertain significance	not provided	2024-10-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg552*) in the PPM1D gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acid(s) of the PPM1D protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of PPM1D-related conditions and/or developmental delay and/or autism (PMID: 33057194, 35982159, 37183572). This variant is also known as 17:58740749C>T. ClinVar contains an entry for this variant (Variation ID: 620148). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PPM1D function (PMID: 23907125, 30388424). 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.
Biotechnology, Institute of Science, Nirma University	RCV003482153	SCV004227963	uncertain significance	Lung carcinoma	2022-04-03	no assertion criteria provided	clinical testing	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