10-87952137-A-G

Variant names:

• chr10-87952137-A-G
• rs786204865
• NM_000314.8:c.512A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000314.8(PTEN):​c.512A>G​(p.Gln171Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q171H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 U:2
• Conservation: PhyloP100: 8.82
• Publications: 18 publications found

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]

PTEN Gene-Disease associations (from GenCC):

• Cowden syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• PTEN hamartoma tumor syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• macrocephaly-autism syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• leiomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bannayan-Riley-Ruvalcaba syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lhermitte-Duclos disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Proteus-like syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glioma susceptibility 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 26 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 28 uncertain in NM_000314.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-87952138-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3707469.
• PP2: Missense variant in the PTEN gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 209 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 3.4883 (above the threshold of 3.09). Trascript score misZ: 4.1129 (above the threshold of 3.09). GenCC associations: The gene is linked to leiomyosarcoma, renal cell carcinoma, Cowden syndrome 1, macrocephaly-autism syndrome, glioma susceptibility 2, PTEN hamartoma tumor syndrome, Cowden disease, Bannayan-Riley-Ruvalcaba syndrome, Proteus-like syndrome, Lhermitte-Duclos disease, activated PI3K-delta syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 10-87952137-A-G is Pathogenic according to our data. Variant chr10-87952137-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 189412.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.512A>G	p.Gln171Arg	missense_variant	Exon 6 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1031A>G	p.Gln344Arg	missense_variant	Exon 7 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.-80A>G		5_prime_UTR_variant	Exon 6 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.512A>G	p.Gln171Arg	missense_variant	Exon 6 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:1 Uncertain:1

Aug 01, 2025

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_000314.8(PTEN):c.512A>G (p.Gln171Arg) is currently classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM6_met De novo (without paternity & maternity confirmed) SCV001757442.1: Gdx #1: de novo via targeted testing in female infant with macrocephaly, dev delays. PM6 (peds score of 4) PS3_moderate Mighell et al. 2018 PMID: 29706350: Lipid phosphatase activity score, -3.85 (TRUE and functionally deleterious). No additional weight was added but in Matreyek et al. 2018 (PMID: 29785012) the abundance class was low PP2_met Missense in gene with low rate of benign missense variants and path. missenses common Missense constraint PP3_met Multiple lines of computational evidence support a deleterious effect on the gene /gene product REVEL score of 0.975 PM2_supporting Absent in population databases PM2_supporting Absent in gnomAD v2 and v4 PS4_supporting Prevalence in affected statistically increased over controls PS4_supporting PMID:39129943: Child at CHOP (ID CHOP-21): patient had clinical features that were convincing enough to treat as PHTS regardless of variant – macrocephaly, vascular malformation, developmental delay / autism spectrum disorder. Peds score of 6, so PS4_P applies for one proband point.

May 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. Experimental studies have shown that this missense change affects PTEN function (PMID: 34943931). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 171 of the PTEN protein (p.Gln171Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PTEN-related conditions (PMID: 22970944, 35227301). ClinVar contains an entry for this variant (Variation ID: 189412). 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.

Prostate cancer;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 Pathogenic:1

Oct 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cowden syndrome 1 Pathogenic:1

Aug 04, 2025

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 38546160, 22970944, 35227301]. Functional studies indicate this variant impacts protein function [PMID: 34943931, 32350270]. This variant is expected to disrupt protein structure [Myriad internal data].

not provided Pathogenic:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Classification criteria: PM2_supporting, PP3, PP2, PS3_moderate, PS2

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 27, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q171R variant (also known as c.512A>G), located in coding exon 6 of the PTEN gene, results from an A to G substitution at nucleotide position 512. The glutamine at codon 171 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in a patient meeting clinical criteria for Cowden syndrome (Pal A et al. N Engl J Med, 2012 Sep;367:1002-11). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). In addition, this variant demonstrated low intracellular protein abundance in a massively parallel functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

not specified Uncertain:1

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		8.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Vest4		0.95
ClinPred		1.0	D
GERP RS		5.7
PromoterAI		0.044	Neutral
Varity_R		0.96
gMVP		1.0
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs786204865; hg19: chr10-89711894; COSMIC: COSV64288519;