Submissions for variant NM_000314.8(PTEN):c.1034T>C (p.Leu345Pro)

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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, Clingen	RCV001216355	SCV002576557	pathogenic	PTEN hamartoma tumor syndrome	2021-06-04	reviewed by expert panel	curation	PTEN c.1034T>C (p.Leu345Pro) 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(s) ClinVar Organization ID: 26957) PM2: Absent in large sequenced populations (PMID 27535533). PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 21659347, internal laboratory contributor(s) ClinVar Organization ID: 26957) PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PS3_P: Abnormal in vitro cellular assay or transgenic model with phenotype different from wild type that does not meet PS3. (PMID 29785012, PMID 29706350)
Ambry Genetics	RCV000575114	SCV000671715	likely pathogenic	Hereditary cancer-predisposing syndrome	2016-02-19	criteria provided, single submitter	clinical testing	The p.L345P variant (also known as c.1034T>C), located in coding exon 9 of the PTEN gene, results from a T to C substitution at nucleotide position 1034. The leucine at codon 345 is replaced by proline, an amino acid with similar properties. This alteration was reported in an individual with MR/DD, papillomatous papules, glycogenic acanthoses, colon polyps and ganglioneuromas and was also present in this individual's father, who was affected with macrocephaly, lipoma, skin tags and penile freckling (Pilarski R et al. J. Med. Genet. 2011 Aug; 48(8):505-12 via personal communication with author). This alteration occurs in the C2 domain of PTEN, and is involved in the ability of PTEN to associate with the surface of the membrane and is involved with the orientation of PTEN towards its substrate (Lee JO et al. Cell. 1999; 99:323-334). In addition, structural analysis reveals that this alteration is more destabilizing than other known mutations in the region, with a ΔΔG of 6.31 kcal (Ambry internal structural analysis). 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 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 200000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be benign yet deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001216355	SCV001388150	uncertain significance	PTEN hamartoma tumor syndrome	2019-04-22	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed in an individual affected with clinical features of Cowden syndrome (PMID: 21659347). ClinVar contains an entry for this variant (Variation ID: 484605). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 345 of the PTEN protein (p.Leu345Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline.

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