Submissions for variant NM_000314.8(PTEN):c.37A>G (p.Lys13Glu)

dbSNP: rs1554890348

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV001269396	SCV001449167	likely pathogenic	Cowden syndrome	2019-02-14	criteria provided, single submitter	clinical testing	ClinGen PTEN Expert Panel Specification v2 used for classification Data included in classification: 1 UK case with macrocephaly, breast cancer at 30, acral keratoses (Cleveland score 34). 3 cases from literature Bubien et al, 2013 (PMID: 23335809). (PS4_mod). Absent from gnomAD (PM2_mod). gnomAD missense Z score =3.49 (PP2_sup). Functional evidence of disruption of nuclear localisation of PTEN resulting in the loss of tumour suppressor activity Gil et al, 2015 (PMID: 25875300), Walker et al, 2004 (PMID: 14711368), Denning et al, 2007 (PMID: 17213812) (PS3_sup). Data not included in classification: In silico: Revel score 0.81 [0-1], CADD scaled score [0-99]: 25.6, other tools suggest variant tolerated.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV002465860	SCV002760191	likely pathogenic	PTEN hamartoma tumor syndrome	2022-10-14	criteria provided, single submitter	curation	Data included in classification: Proband achieves a Cleveland Clinic score of 34, plus additional patient with Cleveland Clinic score of 23 seen in PMID: 23335809 (PS4_sup) Walker et al: p.(Lys13Glu) variant unable to prevent protein kinase B/AKT phosphorylation or inhibit cell proliferation in PTEN null cells and Trotman et al: p.(Lys13Glu) was enriched in the cytoplasm and had defective nuclear import and export. (PS3_sup) Absent from gnomAD v2.1.1 dataset (0/125748 WES) (PM2_mod) REVEL: 0.806 (PP3_sup) PTEN is constrained with a significance Z score (more than 3.09) (PP2_sup) Data not included in classification: Phenotypic features of family members of proband
Labcorp Genetics (formerly Invitae), Labcorp	RCV002465860	SCV004295290	likely pathogenic	PTEN hamartoma tumor syndrome	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 13 of the PTEN protein (p.Lys13Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PTEN hamartoma tumor syndrome (PMID: 23335809, 31130284). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 988004). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTEN protein function. Experimental studies have shown that this missense change affects PTEN function (PMID: 14711368, 25429968, 25875300). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.