10-87933184-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_000314.8(PTEN):c.425G>C(p.Arg142Pro) 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. R142W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.63

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 5 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
• PP2: Missense variant where missense usually causes diseases, PTEN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 10-87933184-G-C is Pathogenic according to our data. Variant chr10-87933184-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 486225.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.425G>C	p.Arg142Pro	missense_variant	5/9	ENST00000371953.8
PTEN	NM_001304717.5	c.944G>C	p.Arg315Pro	missense_variant	6/10
PTEN	NM_001304718.2	c.-326G>C		5_prime_UTR_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.425G>C	p.Arg142Pro	missense_variant	5/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2023

The p.R142P variant (also known as c.425G>C), located in coding exon 5 of the PTEN gene, results from a G to C substitution at nucleotide position 425. The arginine at codon 142 is replaced by proline, an amino acid with dissimilar properties. This alteration has been observed in multiple individuals with clinical features associated with PTEN hamartoma tumor syndrome (Bubien V et al. J Med Genet, 2013 Apr;50:255-63; Fardal Ø et al. Clin Adv Periodontics, 2023 Mar;13:21-26). This alteration has also been observed in at least one individual with a personal and/or family history that is consistent with PTEN hamartoma tumor syndrome (Ambry internal data). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). This variant also demonstrated low intracellular protein abundance in a massively parallel functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). Based on internal structural analysis, R142P is moderately destabilizing to the phosphatase domain (Lee CU et al. Angew Chem Int Ed Engl, 2015 Nov;54:13796-800; Han SY et al. Cancer Res, 2000 Jun;60:3147-51; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.88
Sift	Benign	0.20	T
Sift4G	Benign	0.34	T
Polyphen		1.0	D
Vest4		0.97
MutPred		0.66		Loss of MoRF binding (P = 0.0278);
MVP		0.97
MPC		2.6
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs753630034; hg19: chr10-89692941; COSMIC: COSV100911161;