rs786204910

chr10-87864518-C-Gchr10-87864518-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The NM_000314.8(PTEN):c.49C>G(p.Gln17Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q17R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:2
• Conservation: PhyloP100: 7.07

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 6 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000314.8
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PTEN
• PP5: Variant 10-87864518-C-G is Pathogenic according to our data. Variant chr10-87864518-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 480386.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.49C>G	p.Gln17Glu	missense_variant	1/9	ENST00000371953.8
PTEN	NM_001304717.5	c.568C>G	p.Gln190Glu	missense_variant	2/10
PTEN	NM_001304718.2	c.-657C>G		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.49C>G	p.Gln17Glu	missense_variant	1/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2020

Reported in association with Cowden or Cowden-like syndrome (Nizialek et al., 2015); Published functional studies demonstrate that Q17E modestly stimulated nuclear localization, increased the PIP3 phosphatase activity of PTEN, and could not rescue developmental defects in PTEN-Dictyostelium cells compared to the wildtype (Nguyen et al., 2014); Published functional studies in cell lines demonstrate that Q17E promotes nuclear localization of PTEN compared to wildtype (Mingo et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29706633, 25669429, 26216063, 24979808) -

Macrocephaly-autism syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

May 15, 2024

- -

PTEN hamartoma tumor syndrome Uncertain:1

Uncertain significance, reviewed by expert panel

curation

Clingen PTEN Variant Curation Expert Panel, Clingen

Oct 11, 2023

NM_000314.8(PTEN):c.49C>G (p.Gln17Glu) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (internal laboratory contributor) PS3_P: Other studies demonstrating lipid phosphatase activity <50% of wild-type or abnormal in vitro cellular assay or transgenic model with phenotype different from wild-type that does not meet PS3_moderate. (PMIDs: 24292679, 29706633). PM2_P: Absent in gnomAD PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. BP4: REVEL score < 0.5 (score=0.498) Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 benign supporting, 1 pathogenic moderate, 3 pathogenic supporting codes get -1 + 2 + (1*3) points; total is 4 (Uncertain significance). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2017

The p.Q17E variant (also known as c.49C>G), located in coding exon 1 of the PTEN gene, results from a C to G substitution at nucleotide position 49. The glutamine at codon 17 is replaced by glutamic acid, an amino acid with highly similar properties. This variant, referred to as c.49C>G, has been detected in a cohort of patients who met clinical diagnostic criteria for Cowden syndrome (CS) or relaxed clinical diagnostic criteria for CS-like (Nizialek EA et al. Eur. J. Hum. Genet. 2015 Nov;23:1538-43). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	24
Dann	Benign	0.92
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	0.087
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.50
Sift	Benign	0.21	T
Sift4G	Benign	0.21	T
Polyphen		0.020	B
Vest4		0.53
MutPred		0.40		Loss of MoRF binding (P = 0.0755);
MVP		0.96
MPC		2.0
ClinPred		0.70	D
GERP RS		5.0
Varity_R		0.48
gMVP		0.82

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: rs786204910; hg19: chr10-89624275;