ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.-834C>T (rs587779994)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000732321 SCV000149480 uncertain significance not provided 2018-07-30 criteria provided, single submitter clinical testing This variant is denoted PTEN c.-835C>T, and describes a nucleotide substitution 835 base pairs upstream of the ATG translational start site in the PTEN promoter region. The surrounding sequence, with the base that is substituted in brackets, is TCCT[C/T]TCGG. This variant, also denoted c.-834C>T using alternate numbering, has been reported previously in at least four patients reportedly meeting either a 'relaxed' or classic diagnostic criteria for Cowden syndrome per the International Cowden Consortium criteria (Teresi 2007, Ngeow 2011). However, functional studies did not identify any transcriptional or translational modifications affecting PTEN protein expression (Teresi 2007). Variants within the PTEN promoter have been observed in individuals with features of Cowden syndrome (Zhou 2003). Based on currently available evidence, it is unclear whether PTEN c.-835C>T is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115571 SCV000185191 uncertain significance Hereditary cancer-predisposing syndrome 2013-12-10 criteria provided, single submitter clinical testing
Counsyl RCV000662492 SCV000785004 uncertain significance Cowden syndrome 1 2017-03-13 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000732321 SCV000860257 uncertain significance not provided 2018-03-30 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763683 SCV000894563 uncertain significance Macrocephaly/autism syndrome; Meningioma, familial; Malignant tumor of prostate; VACTERL association with hydrocephalus; Glioma susceptibility 2; PTEN hamartoma tumor syndrome; Cowden syndrome 1 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000732321 SCV001148035 uncertain significance not provided 2019-05-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193512 SCV001362398 uncertain significance not specified 2019-08-13 criteria provided, single submitter clinical testing Variant summary: PTEN c.-835C>T (also known as c.-834C>T) is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 3.2e-05 in 31232 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-835C>T has been reported in the literature in individuals affected with Cowden Syndrome (Zhou_2003, Teresi_2007, Ngeow_2011, Tan_2011, Liu_2013 Ngeow_2014, Nizialek_2015). These reports do not provide unequivocal conclusions about association of the variant with Cowden Syndrome. Although, one study, Black_2017, indicates the variant to have been observed in 10 controls, however, the nature of this cohort is not entirely clear other than stating the individuals did not have a personal history of cancer (ie, age or family history not provided). In addition, a functional study, Teresi_2007 found the variant to not have an impact on PTEN protein expression. Four ClinVar submissions (evaluation after 2014) cites the variant as uncertain significance. Due to the conflicting nature of this variant being observed in many affected individuals but also in controls from a publication, although gnomAD only cites one control and no observed functional impact, the variant is classified as a VUS.

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