chr10-87957973-A-T

Position:

• chr10-87957973-A-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000314.8(PTEN):​c.755A>T​(p.Asp252Val) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P: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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a strand (size 21) in uniprot entity PTEN_HUMAN there are 7 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 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). The gene has 209 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. GenCC has associacion of the 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, 0.984
• PP5: Variant 10-87957973-A-T is Pathogenic according to our data. Variant chr10-87957973-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 575811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87957973-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.755A>T	p.Asp252Val	missense_variant	7/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1274A>T	p.Asp425Val	missense_variant	8/10		NP_001291646.4
PTEN	NM_001304718.2	c.164A>T	p.Asp55Val	missense_variant	7/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.755A>T	p.Asp252Val	missense_variant	7/9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 252 of the PTEN protein (p.Asp252Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PTEN-related conditions (PMID: 25288137, 25669429; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 575811). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTEN function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTEN function (PMID: 27514801, 29706350, 29785012). This variant disrupts the p.Asp252 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23335809, 25527629, 26579216, 29373119). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2016

The p.D252V variant (also known as c.755A>T), located in coding exon 7 of the PTEN gene, results from an A to T substitution at nucleotide position 755. The aspartic acid at codon 252 is replaced by valine, an amino acid with highly dissimilar properties. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lee JO, et al. Cell 1999 Oct; 99(3):323-34). This alteration was described in a cohort of individuals with autism spectrum disorder (Frazier TW, et al. Mol. Psychiatry 2015 Sep; 20(9):1132-8). Additionally, another amino acid change at the same codon (p.D252G) has been identified in a child with an autism spectrum disorder and macrocephaly as well as in a series suspected-PHTS patients (Spinelli L, et al. J. Med. Genet. 2015 Feb; 52(2):128-34. Pilarski R et al, J. Med. Genet. 2011 Aug; 48(8):505-12. Butler MG et al, J. Med. Genet. 2005 Apr; 42(4):318-21). The p.D252V variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0005% (greater than 200000 alleles tested) in our clinical cohort. This variant was detected in an individual meeting diagnostic criteria for Cowden syndrome (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Cowden syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 13, 2023

Variant summary: PTEN c.755A>T (p.Asp252Val) results in a non-conservative amino acid change in the encoded protein sequence. A different variant at the same codon, c.755A>G (p.Asp252Gly) has been classified as Likely pathogenic/pathogenic supporting the critical relevance of the Aspartate 252 residue to PTEN protein function. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251422 control chromosomes. c.755A>T has been reported in the literature in individuals affected with autism spectrum disorders, PTEN-hamartoma syndrome, Cowden syndrome and in settings of Thyroid nodules (example, Frazier_2015, Kim_2022, Yehia_2022, Nizialek_2015, Quaytman_2022). These data indicate that the variant may be associated with disease. Several studies have reported an impact on PTEN-function, however, these were not weighted in the context of this evaluation. The following publications have been ascertained in the context of this evaluation (PMID: 25288137, 34492006, 36175890, 29785012, 29706350, 25669429, 31232187, 35723418, 31427284, 25527629, 35241692). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-8.3	D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.86		Loss of ubiquitination at K254 (P = 0.0579);.;
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.92
gMVP		0.99

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: rs121909239; hg19: chr10-89717730; COSMIC: COSV64297163;