10-87960913-G-T

Variant names:

• chr10-87960913-G-T
• rs786204875
• NM_000314.8:c.821G>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PP2 PP3_Strong PP5_Very_Strong

The NM_000314.8(PTEN):​c.821G>T​(p.Trp274Leu) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W274S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.56
• Publications: 16 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: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 34 uncertain in NM_000314.8
• PP2: Missense variant in the PTEN gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 209 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 3.4883 (above the threshold of 3.09). Trascript score misZ: 4.1129 (above the threshold of 3.09). GenCC associations: The gene is linked to leiomyosarcoma, renal cell carcinoma, Cowden syndrome 1, macrocephaly-autism syndrome, glioma susceptibility 2, PTEN hamartoma tumor syndrome, Cowden disease, Bannayan-Riley-Ruvalcaba syndrome, Proteus-like syndrome, Lhermitte-Duclos disease, activated PI3K-delta syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 10-87960913-G-T is Pathogenic according to our data. Variant chr10-87960913-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 427600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.821G>T	p.Trp274Leu	missense_variant	Exon 8 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1340G>T	p.Trp447Leu	missense_variant	Exon 9 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.230G>T	p.Trp77Leu	missense_variant	Exon 8 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.821G>T	p.Trp274Leu	missense_variant	Exon 8 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes AF: 0.0000213 AC: 3 AN: 140826 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000532

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: 0.0000153

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1447056 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 719404

African (AFR) AF: 0.00 AC: 0 AN: 32632

American (AMR) AF: 0.00 AC: 0 AN: 42690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25712

East Asian (EAS) AF: 0.00 AC: 0 AN: 39250

South Asian (SAS) AF: 0.00 AC: 0 AN: 83068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105338

Other (OTH) AF: 0.00 AC: 0 AN: 59640

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000213 AC: 3 AN: 140826 Hom.: 0 Cov.: 31 AF XY: 0.0000147 AC XY: 1 AN XY: 67928

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000532 AC: 2 AN: 37576

American (AMR) AF: 0.00 AC: 0 AN: 13890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3396

East Asian (EAS) AF: 0.00 AC: 0 AN: 4878

South Asian (SAS) AF: 0.00 AC: 0 AN: 4506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000153 AC: 1 AN: 65372

Other (OTH) AF: 0.00 AC: 0 AN: 1898

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:1

Mar 01, 2017

Herman Laboratory, Nationwide Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Jul 13, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate phosphatase activity similar to wildtype, but impaired protein stability, inability to regulate neuronal cell growth or pS6 signaling, and abnormal subcellular localization (Rodriguez-Escudero et al., 2011; Fricano-Kugler et al., 2018; Matreyek et al., 2018; Wong et al., 2020; Post et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 28526761, 32150788, 20533527, 21828076, 29785012, 29373119, 32350270, 29706350, 18626510, 32126783, 31623367)

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	34
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Pathogenic	3.3	M;.
PhyloP100		9.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-12	D;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.84
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.96
gMVP		0.93
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs786204875; hg19: chr10-89720670; COSMIC: COSV106063127;