ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.741dup (p.Pro248fs) (rs587782341)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131274 SCV000186242 pathogenic Hereditary cancer-predisposing syndrome 2015-03-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Strong segregation with disease (lod >3 = >10 meioses)
GeneDx RCV000520431 SCV000616842 pathogenic not provided 2018-08-30 criteria provided, single submitter clinical testing The c.741dupA variant in the PTEN gene has been reported previously in a 52 year-old man and his adult daughter who both had macrocephaly, lipomas, hyperplastic polyps, oral papillomas, glycogenic acanthosis, and thyroid nodules. His daughter also had papillary thyroid carcinoma and breast cysts (Ha et al., 2013). The c.741dupA variant is also reported as pathogenic in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000186242.4; Landrum et al., 2016). The c.741dupA variant causes a frameshift starting with codon Proline 248, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.P248TfsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.741dupA variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.741dupA as a pathogenic variant
Invitae RCV000541432 SCV000645616 pathogenic PTEN hamartoma tumor syndrome 2018-05-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Pro248Thrfs*5) in the PTEN gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Proteus syndrome or Cowden syndrome  (PMID: 15372512, 23423780). ClinVar contains an entry for this variant (Variation ID: 142259). Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). For these reasons, this variant has been classified as Pathogenic.

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