10-87864518-C-G

Variant names:

• chr10-87864518-C-G
• rs786204910
• NM_000314.8:c.49C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PP2 PM2_Supporting BP4 PS3_Supporting PM6

This summary comes from the ClinGen Evidence Repository: NM_000314.8(PTEN):c.49C>G (p.Gln17Glu) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (internal laboratory contributor)PS3_P: Other studies demonstrating lipid phosphatase activity <50% of wild-type or abnormal in vitro cellular assay or transgenic model with phenotype different from wild-type that does not meet PS3_moderate. (PMIDs: 24292679, 29706633).PM2_P: Absent in gnomADPP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.BP4: REVEL score < 0.5 (score=0.498)Using the Bayesian point system (PMID:29300386) for this variant with conflicting evidence: 1 benign supporting, 1 pathogenic moderate, 3 pathogenic supporting codes get -1 + 2 + (1*3) points; total is 4 (Uncertain significance). LINK:https://erepo.genome.network/evrepo/ui/classification/CA377781947/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTEN NM_001304718.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:3
• Conservation: PhyloP100: 7.07
• Publications: 14 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: Uncertain_significance. The variant received 4 ACMG points.

• PS3: 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.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001304718.2. 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.49C>G	p.Gln17Glu	missense	Exon 1 of 9	NP_000305.3
	PTEN	NM_001304718.2		c.-657C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_001291647.1
	PTEN	NM_001304717.5		c.568C>G	p.Gln190Glu	missense	Exon 2 of 10	NP_001291646.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	ENST00000371953.8	TSL:1 MANE Select	c.49C>G	p.Gln17Glu	missense	Exon 1 of 9	ENSP00000361021.3
	PTEN	ENST00000693560.1		c.568C>G	p.Gln190Glu	missense	Exon 2 of 10	ENSP00000509861.1
	PTEN	ENST00000700029.2		c.49C>G	p.Gln17Glu	missense	Exon 1 of 10	ENSP00000514759.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	0.087
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.3	L
PhyloP100		7.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.50
Sift	Benign	0.21	T
Sift4G	Benign	0.21	T
Polyphen		0.020	B
Vest4		0.53
MutPred		0.40		Loss of MoRF binding (P = 0.0755)
MVP		0.96
MPC		2.0
ClinPred		0.70	D
GERP RS		5.0
Varity_R		0.48
gMVP		0.82
Mutation Taster		=13/87	disease causing

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: rs786204910; hg19: chr10-89624275;