10-87933181-A-G

Variant names:

• chr10-87933181-A-G
• rs863224666
• NM_000314.8:c.422A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000314.8(PTEN):​c.422A>G​(p.His141Arg) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• 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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a helix (size 12) in uniprot entity PTEN_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000314.8
• PM2: Very rare variant in population databases, with high coverage
• 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 Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, macrocephaly-autism syndrome, Cowden syndrome 1, Cowden disease, Proteus-like syndrome, leiomyosarcoma, activated PI3K-delta syndrome, PTEN hamartoma tumor syndrome, glioma susceptibility 2, renal cell carcinoma.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.422A>G	p.His141Arg	missense_variant	Exon 5 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.941A>G	p.His314Arg	missense_variant	Exon 6 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.-329A>G		5_prime_UTR_variant	Exon 4 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.422A>G	p.His141Arg	missense_variant	Exon 5 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

PTEN hamartoma tumor syndrome Uncertain:2

Jul 25, 2019

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTEN c.422A>G (p.His141Arg) variant is a missense variant that has been reported in a cohort of 1012 Cowden syndrome patients meeting relaxed International Cowden Consortium criteria (Nizialiek et al. 2015) and in a heterozygous state in an individual with breast cancer (Chong et al. 2014). No additional clinical or family details were provided in either case. The p.His141Arg variant is absent from the Genome Aggregation Database in a region of good sequencing coverage. It is therefore presumed to be rare. This variant is located within the highly conserved phosphatase domain of the PTEN protein. Missense changes within this domain have been shown to eliminate or reduce phosphatase activity (Han et al. 2000). However, functional studies of the p.His141Arg variant have not been conducted. Missense variants in this domain have been identified in patients (Ali et al. 1999; Eng et al. 2003), but other missense changes affecting His141 have not been reported in the primary literature. Based on the collective evidence, the p.His141Arg variant is classified as a variant of uncertain significance for PTEN hamartoma tumor syndrome. -

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 141 of the PTEN protein (p.His141Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PTEN-related conditions (PMID: 25669429). ClinVar contains an entry for this variant (Variation ID: 418438). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTEN protein function. This variant disrupts the p.His141 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29706350, 29785012; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Pathogenic:1

Dec 06, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in multiple families with features consistent with PTEN Hamartoma Tumor syndrome referred for genetic testing at GeneDx and in published literature (PMID: 25669429); 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: 14566704, 24830819, 29706350, 24475377, 32442409, 25669429) -

Hereditary cancer-predisposing syndrome Uncertain:1

Jul 15, 2013

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

There is insufficient or conflicting evidence for classification of this alteration. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.9	L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.072	T
Polyphen		1.0	D
Vest4		0.89
MutPred		0.57		Gain of MoRF binding (P = 0.0116);
MVP		0.94
MPC		1.8
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.97
gMVP		0.96

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: rs863224666; hg19: chr10-89692938;