ClinVar

Description

The c.1212A>C variant (also known as p.*404CEXT*8), located in coding exon 9 of the PTEN gene, results from an A to C 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 and 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). Another similar alteration, p.*404Cext*8 (c.1212A>T), has been confirmed de novo in a child with clinical features of PTEN hamartoma tumor syndrome (Ambry internal data, correspondence with external laboratory). 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). Additionally this variant has been confirmed as a de novo alteration (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.