10-87960984-C-G

Variant names:

• chr10-87960984-C-G
• rs371387815
• NM_000314.8:c.892C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. PP2 BS1_Supporting BS3_Supporting BP4

This summary comes from the ClinGen Evidence Repository: NM_000314.8(PTEN):c.892C>G (p.Gln298Glu) meets criteria to be classified as likely benign 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). BS1_Supporting: Filtering allele frequency of 0.00002132 (0.002132%, 4/24900 African/African American alleles) in gnomAD. BS3_Supporting: Massively parallel functional assay interrogating phosphatase activity demonstrating no statistically significant difference from wild type (PMID:29706350). BP4: REVEL score = 0.229. PP2: 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.Variant with benign and pathogenic codes. Classification based on application of Bayesian Classification Framework (PMID:29300386): BS1_P (-1 pt1), BS3_P (-1 pt), BP4 (-1 pt), PP2 (+1 pt) = -2 pts total (Likely Benign). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000623/MONDO:0017623/003

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Likely benign reviewed by expert panel U:17 B:3
• Conservation: PhyloP100: 2.69
• Publications: 39 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: Likely_benign. The variant received -2 ACMG points.

• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.892C>G	p.Gln298Glu	missense	Exon 8 of 9	NP_000305.3
	PTEN	NM_001304717.5		c.1411C>G	p.Gln471Glu	missense	Exon 9 of 10	NP_001291646.4
	PTEN	NM_001304718.2		c.301C>G	p.Gln101Glu	missense	Exon 8 of 9	NP_001291647.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	ENST00000371953.8	TSL:1 MANE Select	c.892C>G	p.Gln298Glu	missense	Exon 8 of 9	ENSP00000361021.3	P60484-1
	PTEN	ENST00000693560.1		c.1411C>G	p.Gln471Glu	missense	Exon 9 of 10	ENSP00000509861.1	A0A8I5KSF9
	PTEN	ENST00000700029.2		c.985C>G	p.Gln329Glu	missense	Exon 9 of 10	ENSP00000514759.2	A0A8V8TPK6

Frequencies

GnomAD3 genomes AF: 0.0000862 AC: 13 AN: 150804 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251224 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461450 Hom.: 0 Cov.: 36 AF XY: 0.0000289 AC XY: 21 AN XY: 727038

African (AFR) AF: 0.000269 AC: 9 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111784

Other (OTH) AF: 0.0000497 AC: 3 AN: 60360

GnomAD4 genome AF: 0.0000862 AC: 13 AN: 150804 Hom.: 0 Cov.: 31 AF XY: 0.0000817 AC XY: 6 AN XY: 73416

African (AFR) AF: 0.000171 AC: 7 AN: 41012

American (AMR) AF: 0.000132 AC: 2 AN: 15102

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67844

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	4	-	Cowden syndrome 1 (4)
-	1	2	Hereditary cancer-predisposing syndrome (3)
-	3	-	not specified (3)
-	2	1	PTEN hamartoma tumor syndrome (3)
-	2	-	not provided (2)
-	1	-	Bannayan-Riley-Ruvalcaba syndrome;C0376358:Prostate cancer;C0476089:Endometrial carcinoma;C1168401:Squamous cell carcinoma of the head and neck;C1835047:Melanoma, cutaneous malignant, susceptibility to, 1;C1848599:VACTERL with hydrocephalus;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;C4225426:Thyroid cancer, nonmedullary, 2;CN072330:Cowden syndrome 1 (1)
-	1	-	Familial cancer of breast (1)
-	1	-	Familial ovarian cancer (1)
-	1	-	Glioma susceptibility 2 (1)
-	1	-	PTEN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.069
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	0.92	L
PhyloP100		2.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.42
MVP		0.71
MPC		1.2
ClinPred		0.086	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.62
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs371387815; hg19: chr10-89720741;