chr10-87960922-C-G

Variant names:

• chr10-87960922-C-G
• rs398123329
• NM_000314.8:c.830C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS3 PP1_Moderate PM2 PP2

This summary comes from the ClinGen Evidence Repository: PTEN c.830C>G (p.Thr277Arg) meets criteria to be classified as likely 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).PS3: Phosphatase activity <50% of wild type (PMID 29706350)PM2: Absent in large sequenced populationsPP1_M: Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed. (PMID 23335809)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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA377485523/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 31)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• 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 Likely_pathogenic. Variant got 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.830C>G	p.Thr277Arg	missense_variant	Exon 8 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1349C>G	p.Thr450Arg	missense_variant	Exon 9 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.239C>G	p.Thr80Arg	missense_variant	Exon 8 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.830C>G	p.Thr277Arg	missense_variant	Exon 8 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:2

Mar 23, 2020

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

PTEN c.830C>G (p.Thr277Arg) meets criteria to be classified as likely 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). PS3: Phosphatase activity <50% of wild type (PMID 29706350) PM2: Absent in large sequenced populations PP1_M: Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed. (PMID 23335809) 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. -

Jan 03, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in several individuals affected with PTEN-related conditions (PMID: 20712882, 23335809). ClinVar contains an entry for this variant (Variation ID: 428268). For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect PTEN protein function (PMID: 29706350). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with arginine at codon 277 of the PTEN protein (p.Thr277Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. -

Cowden syndrome 1 Pathogenic:1

Oct 02, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29785012]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23335809]. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Apr 15, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T277R variant (also known as c.830C>G), located in coding exon 8 of the PTEN gene, results from a C to G substitution at nucleotide position 830. The threonine at codon 277 is replaced by arginine, an amino acid with similar properties. This alteration was detected in the germline of an individual diagnosed with Cowden syndrome (CS) and breast cancer. This individual's tumor was noted to have an expression profile similar to that of other CS breast tumors, and absent PTEN IHC expression (Banneau G, Breast Cancer Res. 2010;12(4):R63). This residue occurs in a match for a FHA domain consensus recognition sequence, suggesting that it is a potential binding site (Okumura K et al. Proc. Natl. Acad. Sci. U.S.A. 2005 Feb;102(8):2703-6). In addition, the destabilizing energy of this variant is significantly greater than a known pathogenic variant in the same amino acid position (Ambry internal data). 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 6480 samples (12960 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 deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.7	D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.88		Gain of MoRF binding (P = 0.0289);.;
MVP		1.0
MPC		2.5
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: COSV64300125;