10-87961113-T-G

Position:

• chr10-87961113-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM2 PP2 PP3_Strong PP5

The NM_000314.8(PTEN):​c.1021T>G​(p.Phe341Val) 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.57

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 10 ACMG points.

• PS1: Transcript NM_000314.8 (PTEN) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• 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, 0.96
• PP5: Variant 10-87961113-T-G is Pathogenic according to our data. Variant chr10-87961113-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 495806.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.1021T>G	p.Phe341Val	missense_variant	8/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1540T>G	p.Phe514Val	missense_variant	9/10		NP_001291646.4
PTEN	NM_001304718.2	c.430T>G	p.Phe144Val	missense_variant	8/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.1021T>G	p.Phe341Val	missense_variant	8/9	1	NM_000314.8	ENSP00000361021	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

Alfa AF: 0.274 Hom.: 1568

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cowden syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Oct 09, 2023

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 26302789]. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 06, 2017

Variant summary: The PTEN c.1021T>G (p.Phe341Val) variant involves the alteration of a conserved nucleotide located in the C2 domain. 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 120464 control chromosomes. While the variant has been reported as a somatic mutation in various tumor types in the literature, it has not, to our knowledge, been reported as a germline mutation in affected invidivuals via publications, databases, or clinical labs. Functional studies show the variant to alter phosphoinositol phosphatase activity, show reduced activity in a yeast based-transactivation assay, and result in the complete loss of binding to PICT-1 (Han_2010, Kato_2000, Okahara_2004). Additionally, a knockout mouse model harboring this variant showed heterozygous mice develop carcinoma in the thymus, stomach, adrenal medulla, and mammary gland but not in other organs typically sensitive to Pten deficiency including the thyroid, prostate and uterus (Castera_2015). Although the study did not provide any primary evidence supporting the loss or lack thereof of the phosphatase activity on tissue homogenates, based on the viability of knock out embryos in the absence of overt AKT activation, the authors postulated that this missense variant (p.F341V) disrupts a function that is distinct from the well-established lipid phosphatase function of PTEN. Therefore, the effect of this variant on the established role of PTEN as a tumor suppressor through its lipid phosphatase activity leading to a negative regulation of the PI3K/Akt pathway is not clearly established. Furthermore, to our knowledge, functional assays reproducing the altered phosphatase activity on patient tissue or mammalian models have not been reported at the time of this review. In the absence of clinical information, the variant is classified as a variant of uncertain significance-possibly pathogenic until additional information becomes available. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.3	D;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.010	D;.
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.86		Loss of stability (P = 0.017);.;
MVP		0.91
MPC		2.5
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.86

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: rs1554825652; hg19: chr10-89720870; COSMIC: COSV64288696;