10-87932974-GTTTT-GTTTTT

Variant names:

• chr10-87932974-G-GT
• rs77494260
• NM_000314.8:c.254-30dupT

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.254-30dup (IVS4-30dup) meets criteria to be classified as benign 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).BA1: Allele frequency of 0.01437 (1.437%, 3748/260,738 alleles) in the gnomAD cohort. (PMID 27535533) LINK:https://erepo.genome.network/evrepo/ui/classification/CA146028/MONDO:0017623/003

• Frequency:
  • Genomes: 𝑓 0.010 (19 hom., cov: 32)
  • Exomes 𝑓: 0.014 (112 hom.)
• Consequence: PTEN NM_000314.8 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:5
• Conservation: PhyloP100: 1.19
• Publications: 1 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: 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.254-30dupT		intron	N/A	NP_000305.3
	PTEN	NM_001304717.5		c.773-30dupT		intron	N/A	NP_001291646.4
	PTEN	NM_001304718.2		c.-497-30dupT		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.254-39_254-38insT		intron	N/A	ENSP00000361021.3
	PTEN	ENST00000693560.1		c.773-39_773-38insT		intron	N/A	ENSP00000509861.1
	PTEN	ENST00000700029.2		c.254-39_254-38insT		intron	N/A	ENSP00000514759.2

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1571 AN: 151410 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00994

Gnomad ASJ AF: 0.0344

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.0155

GnomAD2 exomes AF: 0.0147 AC: 3371 AN: 229604 AF XY: 0.0159

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.0385

Gnomad EAS exome AF: 0.000118

Gnomad FIN exome AF: 0.0216

Gnomad NFE exome AF: 0.0157

Gnomad OTH exome AF: 0.0180

GnomAD4 exome AF: 0.0137 AC: 17934 AN: 1311240 Hom.: 112 Cov.: 23 AF XY: 0.0140 AC XY: 9255 AN XY: 659250

African (AFR) AF: 0.00315 AC: 95 AN: 30204

American (AMR) AF: 0.0104 AC: 457 AN: 43894

Ashkenazi Jewish (ASJ) AF: 0.0350 AC: 873 AN: 24964

East Asian (EAS) AF: 0.000494 AC: 19 AN: 38486

South Asian (SAS) AF: 0.0173 AC: 1427 AN: 82304

European-Finnish (FIN) AF: 0.0200 AC: 1040 AN: 52070

Middle Eastern (MID) AF: 0.0351 AC: 192 AN: 5470

European-Non Finnish (NFE) AF: 0.0133 AC: 13005 AN: 978634

Other (OTH) AF: 0.0150 AC: 826 AN: 55214

GnomAD4 genome AF: 0.0104 AC: 1570 AN: 151528 Hom.: 19 Cov.: 32 AF XY: 0.00997 AC XY: 739 AN XY: 74088

African (AFR) AF: 0.00191 AC: 79 AN: 41346

American (AMR) AF: 0.00993 AC: 151 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.0344 AC: 119 AN: 3460

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0140 AC: 67 AN: 4800

European-Finnish (FIN) AF: 0.0162 AC: 170 AN: 10486

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.0139 AC: 944 AN: 67754

Other (OTH) AF: 0.0148 AC: 31 AN: 2090

Alfa AF: 0.0119 Hom.: 1

Bravo AF: 0.00991

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs77494260; hg19: chr10-89692731; COSMIC: COSV100909132;