rs375709098

Variant names:

• chr10-87965321-C-A
• rs375709098
• NM_000314.8:c.1061C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-87965321-C-A
• chr10-87965321-C-G
• chr10-87965321-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2 BS3_Supporting BP4 BS1

This summary comes from the ClinGen Evidence Repository: NM_000314.8(PTEN):c.1061C>A (p.Pro354Gln) variant 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: To be applied for variants with filtering allele frequency (FAF) of 0.000043 up to 0.00056 (0.0043% up to 0.056%) in gnomAD. Popmax FAF of this variant=0.0001051.BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function. This variant: score of 0.09 (WT-like range) on high throughput phosphatase assay (PMID:29706350).BP4: REVEL score < 0.5 (score=0.497).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.Using the Bayesian point system (PMID:29300386) for this variant with conflicting evidence: 1 benign strong and 2 benign supporting = -6. 1 pathogenic supporting = 1. Total = – 5 (likely benign). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000275/MONDO:0017623/003

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Likely benign reviewed by expert panel U:13 B:9
• Conservation: PhyloP100: 5.59
• Publications: 23 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: Likely_benign. The variant received -5 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.1061C>A	p.Pro354Gln	missense	Exon 9 of 9	NP_000305.3
	PTEN	NM_001304717.5		c.1580C>A	p.Pro527Gln	missense	Exon 10 of 10	NP_001291646.4
	PTEN	NM_001304718.2		c.470C>A	p.Pro157Gln	missense	Exon 9 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.1061C>A	p.Pro354Gln	missense	Exon 9 of 9	ENSP00000361021.3	P60484-1
	PTEN	ENST00000693560.1		c.1580C>A	p.Pro527Gln	missense	Exon 10 of 10	ENSP00000509861.1	A0A8I5KSF9
	PTEN	ENST00000700029.2		c.1154C>A	p.Pro385Gln	missense	Exon 10 of 10	ENSP00000514759.2	A0A8V8TPK6

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152018 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000817 AC: 20 AN: 244884 AF XY: 0.0000756

Gnomad AFR exome AF: 0.000128

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: 0.000164

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000123 AC: 180 AN: 1457490 Hom.: 0 Cov.: 33 AF XY: 0.000119 AC XY: 86 AN XY: 724668

African (AFR) AF: 0.0000599 AC: 2 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.00 AC: 0 AN: 85710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000154 AC: 171 AN: 1109406

Other (OTH) AF: 0.000116 AC: 7 AN: 60164

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152018 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74252

African (AFR) AF: 0.0000242 AC: 1 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68006

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000185 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000577 AC: 7

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	3	Hereditary cancer-predisposing syndrome (4)
-	4	-	not provided (4)
-	1	3	not specified (4)
-	2	1	Cowden syndrome 1 (3)
-	1	2	PTEN hamartoma tumor syndrome (3)
-	1	-	Breast and/or ovarian cancer (1)
-	1	-	Malignant tumor of breast (1)
-	1	-	Prostate cancer;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 (1)
-	1	-	PTEN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.083	D
MutationAssessor	Benign	0.55	N
PhyloP100		5.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.50
Sift	Uncertain	0.027	D
Sift4G	Benign	0.14	T
Polyphen		0.47	P
Vest4		0.73
MVP		0.97
MPC		1.1
ClinPred		0.11	T
GERP RS		5.3
Varity_R		0.096
gMVP		0.28
Mutation Taster		=17/83	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: rs375709098; hg19: chr10-89725078; COSMIC: COSV105289735;