10-87957941-T-G

Variant names:

• chr10-87957941-T-G
• rs17849090
• NM_000314.8:c.723T>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 20P and 1B. PS1_Very_Strong PS3 PM1 PM2 PM5 PP2 PP5 BP4

The NM_000314.8(PTEN):​c.723T>G​(p.Phe241Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000580040: This variant demonstrated low intracellular protein abundance in a massively parallel functional assay (Matreyek KA et al. Nat Genet, 2018 06;50:874-882).". Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F241S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.567
• Publications: 17 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 19 ACMG points.

• PS1: Transcript NM_000314.8 (PTEN) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000580040: This variant demonstrated low intracellular protein abundance in a massively parallel functional assay (Matreyek KA et al. Nat Genet, 2018 06;50:874-882).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 32 uncertain in NM_000314.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-87957940-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 7850.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 Cowden syndrome 1, PTEN hamartoma tumor syndrome, macrocephaly-autism syndrome, glioma susceptibility 2, activated PI3K-delta syndrome, Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba syndrome, leiomyosarcoma, Cowden disease, renal cell carcinoma, Proteus-like syndrome.
• PP5: Variant 10-87957941-T-G is Pathogenic according to our data. Variant chr10-87957941-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 428247.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26943767). . Strength limited to SUPPORTING due to the PP5.

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.723T>G	p.Phe241Leu	missense	Exon 7 of 9	NP_000305.3
	PTEN	NM_001304717.5		c.1242T>G	p.Phe414Leu	missense	Exon 8 of 10	NP_001291646.4
	PTEN	NM_001304718.2		c.132T>G	p.Phe44Leu	missense	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.723T>G	p.Phe241Leu	missense	Exon 7 of 9	ENSP00000361021.3	P60484-1
	PTEN	ENST00000693560.1		c.1242T>G	p.Phe414Leu	missense	Exon 8 of 10	ENSP00000509861.1	A0A8I5KSF9
	PTEN	ENST00000700029.2		c.723T>G	p.Phe241Leu	missense	Exon 7 of 10	ENSP00000514759.2	A0A8V8TPK6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461790 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

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

American (AMR) AF: 0.00 AC: 0 AN: 44718

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	PTEN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.57
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.62	N
REVEL	Uncertain	0.55
Sift	Benign	0.58	T
Sift4G	Benign	0.57	T
Polyphen		0.27	B
Vest4		0.86
MutPred		0.49		Gain of sheet (P = 0.1451)
MVP		0.89
MPC		1.4
ClinPred		0.23	T
GERP RS		1.5
Varity_R		0.29
gMVP		0.90
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs17849090; hg19: chr10-89717698;