ClinVar Miner

Submissions for variant NM_000314.6(PTEN):c.-975G>A (rs587780001)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115579 SCV000149488 uncertain significance not specified 2016-11-17 criteria provided, single submitter clinical testing This variant is denoted PTEN c.-976G>A, and describes a nucleotide substitution 976 base pairs upstream of the ATG translational start site in the PTEN promoter region. The surrounding sequence, with the base that is substituted in braces, is CCTC{G/A}GTCT. This variant, published as c.-975G>A using alternate numbering, and other variants within the PTEN promoter region have been observed in individuals with features of Cowden syndrome (Zhou 2003, Nizialek 2015). Based on currently available information, it is unclear whether PTEN c.-976G>A is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587663 SCV000696554 benign not provided 2017-05-15 criteria provided, single submitter clinical testing Variant summary: The PTEN c.-975G>A (also known as c.-976G>A) variant involves the alteration of a non-conserved nucleotide located in the promoter region of PTEN. One in silico tool predicts a benign outcome for this variant. This variant was found in 20/30846 control chromosomes (gnomAD) at a frequency of 0.0006484, which is approximately 104 times the estimated maximal expected allele frequency of a pathogenic PTEN variant (0.0000063), suggesting this variant is likely a benign polymorphism. A publication, Nizialek_2015, cites the variant to have been found in their cohort, however, it is unclear as to whether the variant was found in affected individuals or controls. Although the authors do report another variant at this position, c.-976G>C that segregated with CS in the family and was observed to have promoter methylation, although methylation is commonly associated with C residues. A clinical diagnostic laboratory cites the variant as "uncertain significance." In addition, an internal LCA sample reports the variant to co-occur with a likely pathogenic TP53 variant, c.375+2T>C. Therefore, the variant of interest has been classified as Benign.

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