chr10-87864515-T-G

Position:

• chr10-87864515-T-G

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.46T>G​(p.Tyr16Asp) variant causes a missense change. 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.17

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 domain Phosphatase tensin-type (size 171) in uniprot entity PTEN_HUMAN there are 110 pathogenic changes around while only 5 benign (96%) in NM_000314.8
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.923
• PP5: Variant 10-87864515-T-G is Pathogenic according to our data. Variant chr10-87864515-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 422899.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-87864515-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.46T>G	p.Tyr16Asp	missense_variant	1/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.565T>G	p.Tyr189Asp	missense_variant	2/10		NP_001291646.4
PTEN	NM_001304718.2	c.-660T>G		5_prime_UTR_variant	1/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.46T>G	p.Tyr16Asp	missense_variant	1/9	1	NM_000314.8	ENSP00000361021	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Dec 23, 2016

This variant is denoted PTEN c.46T>G at the cDNA level, p.Tyr16Asp (Y16D) at the protein level, and results in the change of a Tyrosine to an Aspartic Acid (TAT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. However, PTEN Tyr16Cys has been shown to impact phosphatase activity and cellular localization (Han 2000, Kim 2011, Gil 2015), and PTEN Tyr16His has been observed in an individual with breast and endometrial cancer as well as other findings suggestive of PTEN Hamartoma Tumor syndrome (Ngeow 2014). PTEN Tyr16Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Tyrosine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PTEN Tyr16Asp occurs at a position that is conserved across species and is located within the N-terminal nuclear localization signal and the phosphatase domain (Molinari 2014, Gil 2015). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.38	B
Vest4		0.91
MutPred		0.58		Gain of disorder (P = 0.0172);
MVP		1.0
MPC		4.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.87
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: rs1064796078; hg19: chr10-89624272; COSMIC: COSV64294593; COSMIC: COSV64294593;