rs398123318

Variant names:

• chr10-87925557-TGTAA-T
• rs398123318
• NM_000314.8:c.209+4_209+7delAGTA

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM6_Strong PS4_Supporting PS3 PP1_Moderate PM2

This summary comes from the ClinGen Evidence Repository: PTEN c.209+4_209+7delAGTA (IVS3+4_IVS3+7delAGTA) meets criteria to be classified as pathogenic 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).PS3: RNA, mini-gene, or other assay shows impact on splicing. (PMID 28677221)PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (Internal laboratory contributor(s))PM2: Absent in large sequenced populations (PMID 27535533).PP1_M: Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed. (Internal laboratory contributor(s))PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 28677221, internal laboratory contributor(s) SCV000273868.4) LINK:https://erepo.genome.network/evrepo/ui/classification/CA220637/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN ENST00000371953.8 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 9.29
• Publications: 9 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

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000371953.8. 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.209+4_209+7delAGTA		splice_region intron	N/A	NP_000305.3
	PTEN	NM_001304717.5		c.728+4_728+7delAGTA		splice_region intron	N/A	NP_001291646.4
	PTEN	NM_001304718.2		c.-541-5485_-541-5482delAGTA		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.209+1_209+4delGTAA		splice_donor splice_region intron	N/A	ENSP00000361021.3	P60484-1
	PTEN	ENST00000693560.1		c.728+1_728+4delGTAA		splice_donor splice_region intron	N/A	ENSP00000509861.1	A0A8I5KSF9
	PTEN	ENST00000700029.2		c.209+1_209+4delGTAA		splice_donor splice_region intron	N/A	ENSP00000514759.2	A0A8V8TPK6

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	PTEN hamartoma tumor syndrome (2)
1	-	-	Cowden syndrome 1 (1)
1	-	-	Endometrial carcinoma (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not provided (1)
1	-	-	Ovarian neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 0

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

Other links and lift over

dbSNP: rs398123318; hg19: chr10-89685314; COSMIC: COSV64293809;