ClinVar Genomic variation as it relates to human health

This variant is denoted c.491delA at the cDNA level and p.K164RfsX3 at the protein level. Using capital letters to denote exonic sequence and lower case letters to denote intronic sequence, the reference sequence with the base that is deleted in braces is: CAAAA{A}Ggtaag. The c.491delA mutation in the PTEN gene has been reported previously in association with Cowden syndrome, Cowden-like syndrome, and PTEN hamartoma tumor syndrome (Bussaglia et al., 2002; Heindl et at., 2012; Ngeow et al., 2011). Ngeow et al. reported that the c.491delA mutation was present in a patient diagnosed with Cowden/Cowden-like syndrome and thyroid cancer. The deletion causes a frameshift starting with codon Lysine 164, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Lys164ArgfsX3. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in PTEN panel(s).

This sequence change creates a premature translational stop signal (p.Lys164Argfs*3) in the PTEN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with PTEN hamartoma tumor syndrome and Cowden syndrome (PMID: 11918710, 17392703, 21956414, 22266152, 24345843). ClinVar contains an entry for this variant (Variation ID: 189448). For these reasons, this variant has been classified as Pathogenic.

The c.491delA pathogenic mutation, located in coding exon 5 of the PTEN gene, results from a deletion of one nucleotide at nucleotide position 491, causing a translational frameshift with a predicted alternate stop codon (p.K164Rfs*3). This mutation has been identified in multiple individuals/families with Cowden syndrome (Bussaglia E et al. J. Invest. Dermatol. 2002 Apr;118:639-44; Caux F et al. Eur. J. Hum. Genet. 2007 Jul;15:767-73; Ngeow J et al. J. Clin. Endocrinol. Metab. 2011 Dec;96:E2063-71; Smith JR et al. J. Clin. Endocrinol. Metab. 2011 Jan;96:34-7; Heindl M et al. Gastroenterology. 2012 May;142:1093-1096.e6; Ngeow J et al. J. Clin. Oncol. 2014 Jun;32:1818-24; Meric-Bernstam F et al. Ann. Oncol. 2016 May;27:795-800; Chen HH et al. J. Allergy Clin. Immunol. 2017 Feb;139:607-620.e15). Of note, this alteration is also designated as c.487del in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

This c.491del (p.Lys164Argfs*3) frameshift variant in the PTEN gene is absent from public databases and is predicted to result in the loss of function of PTEN. This variant has been observed in multiple unrelated individual with Cowden syndrome/ PTEN hamartoma syndromes (PMID 11918710 , 17392703, 20962022, 21956414, 24778394) and has been shown to segregate with Cowden syndrome in one family (PMID 17392703). . Based on the above evidence, this c.491del (p.Lys164Argfs*3) variant in the PTEN gene is classified as pathogenic.

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.