ClinVar Miner

Submissions for variant NM_000314.8(PTEN):c.830C>T (p.Thr277Ile)

dbSNP: rs398123329
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clingen PTEN Variant Curation Expert Panel, Clingen RCV003454396 SCV004183295 pathogenic PTEN hamartoma tumor syndrome 2023-06-14 reviewed by expert panel curation NM_000314.8(PTEN):c.830C>T (p.Thr277Ile) variant meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (PMID:25549896 and internal laboratory contributor). PS3_M: Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350. 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. PP3: REVEL score > 0.7 (score=0.988) PM2_P: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID: 25549896).
Ambry Genetics RCV000163498 SCV000214056 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-03 criteria provided, single submitter clinical testing The p.T277I variant (also known as c.830C>T), located in coding exon 8 of the PTEN gene, results from a C to T substitution at nucleotide position 830. The threonine at codon 277 is replaced by isoleucine, an amino acid with some similar properties. This variant was reported as de novo (unconfirmed parentage) in a female child followed from birth to age 4 who presented with macrocephaly followed by patent ductus arteriosus, nevus flammeus of the philtrum suggestive of Megalencephaly-Capillary Malformation syndrome, overgrowth, widespread capillary malformations, enlarged cerebral ventricles identified by MRI and speech support was needed for learning disabilities (Busa T et al. Eur J Paediatr Neurol, 2015 Mar;19:188-92). In addition, RNA studies was performed for this variant and no abnormal splicing was reported to be associated (Wai HA et al. Genet Med, 2020 Jun;22:1005-1014). However, in a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was reported to be in the hypomorphic range of functionally abnormal (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV001269397 SCV001449168 likely pathogenic Cowden syndrome 2020-02-14 criteria provided, single submitter clinical testing ClinGen PTEN Expert Panel Specification v2 used for classification. Data included in classification: UK family #1: Paediatric phenotype specificity score 3 (extreme macrocephaly + 2 (autism/dev delay)=5. Literature case #1 Busa et al, 2015 (PMID: 25549896): Paediatric phenotype specificity score 3 (extreme macrocephaly) + 2 (enlarged cerebral ventricles)=5. 2 probands with paediatric specificity score of 5=2 points (PS4_mod). The variant was absent from the gnomAD population (141,456 individuals) (PM2_mod). Literature case #1: de novo in proband (PM6_mod). ExAC constraint score: 3.71, gnomAD constraint score: 3.49 i.e. low benign missense rate (PP2_sup). Data not included in classification: In silico: Revel score 0.988. The variant is in protein domains: Tensin phosphatase, C2 domain, Bifunctional phosphatidylinositol trisphosphate phosphatase/dual specificity phosphatase PTEN C2 domain.
GeneDx RCV001559615 SCV001781885 pathogenic not provided 2020-07-27 criteria provided, single submitter clinical testing Published functional studies demonstrate reduced lipid phosphatase activity (Mighell 2018); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32123317, 25549896, 29706350)
Institute of Human Genetics, University of Leipzig Medical Center RCV003493469 SCV004244350 likely pathogenic Macrocephaly-autism syndrome 2024-01-16 criteria provided, single submitter clinical testing Criteria applied: PS4_MOD,PS2_MOD,PM5,PM2_SUP,PP3,PP2
Invitae RCV003454396 SCV004295320 pathogenic PTEN hamartoma tumor syndrome 2022-11-06 criteria provided, single submitter clinical testing This variant disrupts the p.Thr277 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28263967; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt PTEN protein function. ClinVar contains an entry for this variant (Variation ID: 184277). This missense change has been observed in individual(s) with clinical features of PTEN-related conditions (PMID: 25549896). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 277 of the PTEN protein (p.Thr277Ile).

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