rs555895

Variant names:

• chr10-87961150-T-G
• rs555895
• NM_000314.8:c.1026+32T>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: PTEN c.1026+32T>G (IVS8+32T>G) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BA1: Allele frequency of 0.374 (37.4%, 102,771/274,696 alleles) in the gnomAD cohort. (PMID 27535533) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000255/MONDO:0017623/003

• Frequency:
  • Genomes: 𝑓 0.40 (12672 hom., cov: 31)
  • Exomes 𝑓: 0.36 (93105 hom.)
• Consequence: PTEN NM_000314.8 intron
• Clinical Significance: Benign reviewed by expert panel B:11
• Conservation: PhyloP100: -0.850

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 Benign. Variant got -8 ACMG points.

• BA1: 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.1026+32T>G		intron_variant	Intron 8 of 8	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1545+32T>G		intron_variant	Intron 9 of 9		NP_001291646.4
PTEN	NM_001304718.2	c.435+32T>G		intron_variant	Intron 8 of 8		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.1026+32T>G		intron_variant	Intron 8 of 8	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60661 AN: 151868 Hom.: 12632 Cov.: 31

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.506

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.407

GnomAD3 exomes AF: 0.373 AC: 92706 AN: 248338 Hom.: 17918 AF XY: 0.363 AC XY: 48929 AN XY: 134850

Gnomad AFR exome AF: 0.498

Gnomad AMR exome AF: 0.457

Gnomad ASJ exome AF: 0.371

Gnomad EAS exome AF: 0.489

Gnomad SAS exome AF: 0.309

Gnomad FIN exome AF: 0.344

Gnomad NFE exome AF: 0.335

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.358 AC: 511154 AN: 1426510 Hom.: 93105 Cov.: 28 AF XY: 0.355 AC XY: 252501 AN XY: 711724

Gnomad4 AFR exome AF: 0.508

Gnomad4 AMR exome AF: 0.462

Gnomad4 ASJ exome AF: 0.370

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.307

Gnomad4 FIN exome AF: 0.342

Gnomad4 NFE exome AF: 0.348

Gnomad4 OTH exome AF: 0.375

GnomAD4 genome AF: 0.400 AC: 60753 AN: 151986 Hom.: 12672 Cov.: 31 AF XY: 0.398 AC XY: 29556 AN XY: 74274

Gnomad4 AFR AF: 0.502

Gnomad4 AMR AF: 0.452

Gnomad4 ASJ AF: 0.377

Gnomad4 EAS AF: 0.506

Gnomad4 SAS AF: 0.300

Gnomad4 FIN AF: 0.344

Gnomad4 NFE AF: 0.336

Gnomad4 OTH AF: 0.414

Alfa AF: 0.364 Hom.: 1963

Bravo AF: 0.413

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 06, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30316882) -

not specified Benign:2

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 70% of patients studied by a panel of primary immunodeficiencies. Number of patients: 62. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cowden syndrome 1 Benign:2

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PTEN hamartoma tumor syndrome Benign:2

Sep 14, 2016

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

PTEN c.1026+32T>G (IVS8+32T>G) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). BA1: Allele frequency of 0.374 (37.4%, 102,771/274,696 alleles) in the gnomAD cohort. (PMID 27535533) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Mar 26, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Macrocephaly-autism syndrome Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.69
DANN	Benign	0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs555895; hg19: chr10-89720907; COSMIC: COSV64292683;