10-87933160-T-G

Position:

• chr10-87933160-T-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000314.8(PTEN):​c.401T>G​(p.Met134Arg) 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. 12/21 in silico tools predict a damaging 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. M134L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.62

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTEN. . Gene score misZ 3.4883 (greater than the threshold 3.09). Trascript score misZ 4.1129 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.987
• PP5: Variant 10-87933160-T-G is Pathogenic according to our data. Variant chr10-87933160-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431829.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.401T>G	p.Met134Arg	missense_variant	5/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.920T>G	p.Met307Arg	missense_variant	6/10		NP_001291646.4
PTEN	NM_001304718.2	c.-350T>G		5_prime_UTR_variant	4/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.401T>G	p.Met134Arg	missense_variant	5/9	1	NM_000314.8	ENSP00000361021.3

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

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 14, 2017

The M134R missense variant in the PTEN gene has been reported previously in at least one family with features of Bannayan-Riley-Ruvalcaba syndrome (Figer et al., 2002). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M134R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant at the same residue (M134I) has been reported in association with a PTEN-related disorder, supporting the functional importance of this region of the protein (Busa et al., 2013). Based on currently available evidence, M134R is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.7	H
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.91		Gain of MoRF binding (P = 0.0079);
MVP		0.98
MPC		2.8
ClinPred		1.0	D
GERP RS		5.2
Varity_R		1.0
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1085308046; hg19: chr10-89692917; COSMIC: COSV64299190;