ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.1212A>T (p.Ter404Cys) (rs876660879)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000645070 SCV001244244 pathogenic PTEN hamartoma tumor syndrome 2019-11-22 reviewed by expert panel curation PTEN c.1212A>T (p.Ter404CysextTer8) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (internal laboratory contributor ClinVar Organization ID: 26957) PM2: Absent in large sequenced populations (PMID 27535533). PM4: Variant causes protein extension. PS4_M: Probands with phenotype specificity score of 2-3.5. (internal laboratory contributors ClinVar Organization ID: 26957, SCV000278659.5)
Ambry Genetics RCV000214783 SCV000278659 likely pathogenic Hereditary cancer-predisposing syndrome 2016-08-25 criteria provided, single submitter clinical testing The c.1212A>T variant (also known as p.*404Cext*8), located in coding exon 9 of the PTEN gene, results from an A to T substitution at nucleotide position 1212, which is the last nucleotide of the PTEN gene. The stop codon at position 404 is replaced by cysteine, resulting in an elongation of the protein by 8 amino acids. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data). In one study, a different but similar alteration, c.1211G>C, which replaces the stop codon at position 404 with a serine also results in the elongation of the protein by 8 amino acids was described. This alteration occurred de novo in a 3 year old male with macrocephaly, pervasive developmental disorder, hypotonia, frontal bossing, and enlarged perivascular spaces on neuroimaging (Vanderver A, et al. Am. J. Med. Genet. A 2014;164A(3):627-33). In addition, functional assays for a similar alteration, p.*404Lext*8 (also known as X404L), which replaces the stop codon at position 404 with a leucine, and also results in the elongation of the protein by 8 amino acids, demonstrated this alteration was unable to rescue abnormal morphogenesis in cells depleted of PTEN (Berglund FM, et al. Oncogene 2013 Sep; 32(37):4417-26). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6426 samples (12852 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0003% (greater than 250000 alleles tested) in our clinical cohort. This termination codon is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000645070 SCV000766812 uncertain significance PTEN hamartoma tumor syndrome 2017-11-20 criteria provided, single submitter clinical testing This sequence change disrupts the translational stop signal of the PTEN mRNA. It is expected to extend the length of the PTEN protein by 8 additional amino acid residues. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PTEN-related disease. ClinVar contains an entry for this variant (Variation ID: 234144). A different variant in affecting this stop codon (p.*404Serext*8) has been reported in an individual with macrocephaly, enlarged periventricular spaces and pervasive developmental disorder (PMID: 24375884). This suggests that stop loss variants may impact PTEN protein function. 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.

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