rs587782360

chr10-87933162-A-Gchr10-87933162-A-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000314.8(PTEN):c.403A>G(p.Ile135Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. I135M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.88

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 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 chr10-87933163-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, PTEN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 10-87933162-A-G is Pathogenic according to our data. Variant chr10-87933162-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.403A>G	p.Ile135Val	missense_variant	5/9	ENST00000371953.8
PTEN	NM_001304717.5	c.922A>G	p.Ile308Val	missense_variant	6/10
PTEN	NM_001304718.2	c.-348A>G		5_prime_UTR_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.403A>G	p.Ile135Val	missense_variant	5/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neoplasm of ovary Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Cowden syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Oct 20, 2023

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 17392703, 23335809, 32378608, 37090027]. -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 21, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 135 of the PTEN protein (p.Ile135Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with PTEN hamartoma tumor syndrome and Bannayan-Riley-Ruvalcaba syndrome (PMID: 10400993, 17392703, 23335809). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142287). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt PTEN function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts the p.Ile135 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16894538). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Although published functional studies demonstrate no impact on protein function for the p.I135V missense variant, a potential splice impact has not, to our knowledge, been interrogated (Mighell et al., 2018; Post et al., 2020; Chao et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24609522, 28152038, 23161105, 16894538, 11849740, 11234884, 28188106, 23335809, 21194675, 25527629, 32366478, 32378608, 10400993, 30787465, 34355460, 32350270, 19457929, 24475377, 29706350, 17392703) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2014

The p.I135V pathogenic mutation (also known as c.403A>G), located in coding exon 5 of the PTEN gene, results from an A to G substitution at nucleotide position 403. The isoleucine at codon 135 is replaced by valine, an amino acid with highly similar properties.<span style="background-color: initial;">This alteration has been reported in a case of familial Bannayan-Riley-Ruvalcaba syndrome (BRRS) (Marsh DJ et al. Hum. Mol. Genet. 1999 Aug;8(8):1461-72).<span style="background-color: initial;">This alteration is in the phosphatase domain and approximately 38% of PTEN mutations are in the phosphatase core motif (Eng C et al. Hum Mutat. 2003 Sep;22(3):183-98).<span style="background-color: initial;">Several other mutation have been reported at this amnio acid position in both patients with BRRS and Cowden syndrome (CS) (Tan MH et al.Am J Hum Genet. 2011 Jan 7;88(1):42-56; Boccone L et al. Am. J. Med. Genet. A 2006 Sep;140(18):1965-9).<span style="background-color: initial;">This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6,503 samples (13,006 alleles) with coverage at this position. B<span style="background-color: initial;">ased on the available evidence, p.I135V is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.66	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.57	N
REVEL	Pathogenic	0.82
Sift	Benign	0.25	T
Sift4G	Benign	0.30	T
Polyphen		0.99	D
Vest4		0.68
MutPred		0.90		Gain of MoRF binding (P = 0.1222);
MVP		0.97
MPC		1.6
ClinPred		0.90	D
GERP RS		5.2
Varity_R		0.35
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.64		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587782360; hg19: chr10-89692919; COSMIC: COSV64288466;