Submissions for variant NM_000314.8(PTEN):c.430A>T (p.Lys144Ter)

dbSNP: rs1057520622

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000435296	SCV000516631	pathogenic	not provided	2015-04-06	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted PTEN c.430A>T at the cDNA level and p.Lys144Ter (K144X) at the protein level. The substitution creates a nonsense variant, which changes a Lysine to a premature stop codon (AAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. While This variant has been identified in a case of complex atypical hyperplasia, it has not, to our knowledge, been reported in the literature as a germline pathogenic variant (Hayes 2006). PTEN Lys144Ter is considered pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001058791	SCV001223386	pathogenic	PTEN hamartoma tumor syndrome	2019-12-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant has not been reported in the literature in individuals with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 379501). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys144*) in the PTEN gene. It is expected to result in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194183	SCV001363518	likely pathogenic	Cowden syndrome	2019-11-04	criteria provided, single submitter	clinical testing	Variant summary: PTEN c.430A>T (p.Lys144X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251364 control chromosomes. c.430A>T has been reported in the literature as a druggable mutation identified in the cell free DNA of an individual with metastatic breast cancer (Li_2019). These report(s) do not provide unequivocal conclusions about association of the variant with a germline predisposition to Cowden Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.