rs555895

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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:12
• Conservation: PhyloP100: -0.850
• Publications: 24 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: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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

Specifications for PTEN are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000314.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	NM_000314.8	MANE Select	c.1026+32T>G		intron	N/A	NP_000305.3
	PTEN	NM_001304717.5		c.1545+32T>G		intron	N/A	NP_001291646.4
	PTEN	NM_001304718.2		c.435+32T>G		intron	N/A	NP_001291647.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	ENST00000371953.8	TSL:1 MANE Select	c.1026+32T>G		intron	N/A	ENSP00000361021.3	P60484-1
	PTEN	ENST00000472832.3	TSL:2	c.*23T>G		3_prime_UTR	Exon 8 of 8	ENSP00000483066.2	A0A087X033
	PTEN	ENST00000693560.1		c.1545+32T>G		intron	N/A	ENSP00000509861.1	A0A8I5KSF9

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

GnomAD2 exomes AF: 0.373 AC: 92706 AN: 248338 AF XY: 0.363

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 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

African (AFR) AF: 0.508 AC: 16594 AN: 32678

American (AMR) AF: 0.462 AC: 20593 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 9595 AN: 25940

East Asian (EAS) AF: 0.500 AC: 19725 AN: 39422

South Asian (SAS) AF: 0.307 AC: 26246 AN: 85374

European-Finnish (FIN) AF: 0.342 AC: 18222 AN: 53350

Middle Eastern (MID) AF: 0.408 AC: 2327 AN: 5704

European-Non Finnish (NFE) AF: 0.348 AC: 375647 AN: 1080138

Other (OTH) AF: 0.375 AC: 22205 AN: 59288

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

African (AFR) AF: 0.502 AC: 20795 AN: 41434

American (AMR) AF: 0.452 AC: 6898 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1305 AN: 3464

East Asian (EAS) AF: 0.506 AC: 2622 AN: 5186

South Asian (SAS) AF: 0.300 AC: 1449 AN: 4828

European-Finnish (FIN) AF: 0.344 AC: 3624 AN: 10548

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.336 AC: 22812 AN: 67950

Other (OTH) AF: 0.414 AC: 873 AN: 2110

Alfa AF: 0.382 Hom.: 3937

Bravo AF: 0.413

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Cowden syndrome 1 (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not specified (2)
-	-	2	PTEN hamartoma tumor syndrome (2)
-	-	1	Macrocephaly-autism syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.69
DANN	Benign	0.37
PhyloP100		-0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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