10-87957915-C-T

Variant names:

• chr10-87957915-C-T
• rs121909219
• NM_000314.8:c.697C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000314.8(PTEN):​c.697C>T​(p.Arg233*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000213087: Furthermore, in vitro studies showed a significant reduction in PTEN protein expression while mRNA levels remained comparable to wild-type suggesting post translational protein degradation. Additional in vitro studies showed increased proteasome activity in cells with this mutation compared to wild-type. Authors suggested a possible association with the increased proteasome activity and an increased risk for neurologic manifestations (He et al. Cancer Res. 2013. 73(10):3029-3040)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R233R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTEN NM_000314.8 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:31 O:2
• Conservation: PhyloP100: 1.28
• Publications: 153 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 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000213087: Furthermore, in vitro studies showed a significant reduction in PTEN protein expression while mRNA levels remained comparable to wild-type suggesting post translational protein degradation. Additional in vitro studies showed increased proteasome activity in cells with this mutation compared to wild-type. Authors suggested a possible association with the increased proteasome activity and an increased risk for neurologic manifestations (He et al. Cancer Res. 2013. 73(10):3029-3040).; SCV000222225: Published functional studies demonstrate a damaging effect: decreased PTEN protein expression, increased phosphorylated AKT and ERK in patient cells (He et al., 2013); PMID: 27488391; SCV000604975: Functional studies show that this variant leads to increased proteasomal degradation of PTEN protein (He 2013). He X et al. Cowden syndrome-related mutations in PTEN associate with enhanced proteasome activity. Cancer Res. 2013 May 15;73(10):3029-40.; SCV002774375: Experimental studies indicate the truncated protein is unstable and associated with proteasome hyperactivity (PMID: 23475934 (2013)).; SCV001362393: At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated the lack of the protein including the truncated protein product in transfected cell lines (He_2013).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87957915-C-T is Pathogenic according to our data. Variant chr10-87957915-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 7813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.697C>T	p.Arg233*	stop_gained	Exon 7 of 9	NP_000305.3
	PTEN	NM_001304717.5		c.1216C>T	p.Arg406*	stop_gained	Exon 8 of 10	NP_001291646.4
	PTEN	NM_001304718.2		c.106C>T	p.Arg36*	stop_gained	Exon 7 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.697C>T	p.Arg233*	stop_gained	Exon 7 of 9	ENSP00000361021.3	P60484-1
	PTEN	ENST00000693560.1		c.1216C>T	p.Arg406*	stop_gained	Exon 8 of 10	ENSP00000509861.1	A0A8I5KSF9
	PTEN	ENST00000700029.2		c.697C>T	p.Arg233*	stop_gained	Exon 7 of 10	ENSP00000514759.2	A0A8V8TPK6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461758 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727192

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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111920

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Cowden syndrome 1 (9)
5	-	-	not provided (5)
5	-	-	PTEN hamartoma tumor syndrome (5)
3	-	-	Hereditary cancer-predisposing syndrome (3)
3	-	-	Macrocephaly-autism syndrome (3)
2	-	-	Cowden syndrome (2)
1	-	-	Abnormal cardiovascular system morphology (1)
1	-	-	Gastric cancer (1)
1	-	-	Glioma susceptibility 2 (1)
1	-	-	Ovarian neoplasm (1)
1	-	-	PTEN-related disorder (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.82	D
PhyloP100		1.3
Vest4		0.98
GERP RS		0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs121909219; hg19: chr10-89717672; COSMIC: COSV64288653;