10-87960922-C-T

Position:

• chr10-87960922-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP2 PP3 PM2_Supporting PS3_Moderate PM6_Strong PS4_Supporting

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000207/MONDO:0017623/003

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5 U:1
• Conservation: PhyloP100: 7.53

Genes affected

PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.830C>T	p.Thr277Ile	missense_variant	8/9	ENST00000371953.8
PTEN	NM_001304717.5	c.1349C>T	p.Thr450Ile	missense_variant	9/10
PTEN	NM_001304718.2	c.239C>T	p.Thr80Ile	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.830C>T	p.Thr277Ile	missense_variant	8/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 144834 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 144834 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 69962

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 06, 2022	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). -
Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Jun 14, 2023	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). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2020

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) -

Cowden syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

Feb 14, 2020

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. -

Macrocephaly-autism syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 16, 2024

Criteria applied: PS4_MOD,PS2_MOD,PM5,PM2_SUP,PP3,PP2 -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.7	D;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.82	P;.
Vest4		0.95
MutPred		0.83		Loss of disorder (P = 0.1174);.;
MVP		0.99
MPC		2.4
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.90
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398123329; hg19: chr10-89720679; COSMIC: COSV64291992;