10-87933144-G-C

Variant names:

• chr10-87933144-G-C
• rs786204929
• NM_000314.8:c.385G>C

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000314.8(PTEN):​c.385G>C​(p.Gly129Arg) 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G129E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.53

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 23 ACMG points.

• PS1: Transcript NM_000314.8 (PTEN) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-87933145-G-A is described in Lovd as [Pathogenic].
• 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, 0.988
• PP5: Variant 10-87933144-G-C is Pathogenic according to our data. Variant chr10-87933144-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 804339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.385G>C	p.Gly129Arg	missense_variant	Exon 5 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.904G>C	p.Gly302Arg	missense_variant	Exon 6 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.-366G>C		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.385G>C	p.Gly129Arg	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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cowden syndrome 1 Pathogenic:1

May 23, 2019

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PTEN hamartoma tumor syndrome Pathogenic:1

Feb 15, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported to be de novo an in individual affected with PTEN hamartoma syndrome (PMID: 22469695). ClinVar contains an entry for this variant (Variation ID: 189484). For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Gly129Glu) has been determined to be pathogenic (PMID: 9140396, 21659347, 23399955, 9256433, 10051603). This suggests that the glycine residue is critical for PTEN protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this missense change abrogates PTEN-dependent phosphatase activity and has a moderate effect on cell proliferation and invasiveness (PMID: 9256433, 28497778, 17928923, 25527629). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 129 of the PTEN protein (p.Gly129Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 14, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G129R variant (also known as c.385G>C), located in coding exon 5 of the PTEN gene, results from a G to C substitution at nucleotide position 385. The glycine at codon 129 is replaced by arginine, an amino acid with dissimilar properties. This alteration has demonstrated deficient phosphatase activity compared to wild type controls in multiple in vitro assays (Myers MP et al. Proc. Natl. Acad. Sci. U.S.A., 1997 Aug;94:9052-7; Ramaswamy S et al. Proc. Natl. Acad. Sci. U.S.A. 1999 Mar; 96(5):2110-5; Han SY et al. Cancer Res., 2000 Jun;60:3147-51). Functional analyses of p.G129R have demonstrated PTEN protein stability similar to wild-type; however, it demonstrated a complete inability of the G129R mutated protein to suppress AKT signaling, a key role of PTEN (Spinelli L et al. J. Med. Genet., 2015 Feb;52:128-34). In addition, two mutations at the same codon, p.G129E and p.G129V have been detected in individuals with features of PTEN hamaratoma tumor syndrome (PHTS) (Liaw D et al. Nat. Genet. 1997 May;16:64-7; Pilarski R et al. J. Med. Genet. 2011 Aug;48:505-12; Ngeow J et al. Gastroenterology. 2013 Jun; 144(7):1402-9, 1409.e1-5). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this variant is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.88		Gain of MoRF binding (P = 0.0184);
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs786204929; hg19: chr10-89692901; COSMIC: COSV64309376;