rs1554893812

chr10-87894075-G-Achr10-87894075-G-Cchr10-87894075-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_000314.8(PTEN):c.130G>A(p.Gly44Ser) 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. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G44D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.60

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 hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain 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 chr10-87894076-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 427582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, PTEN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.130G>A	p.Gly44Ser	missense_variant	2/9	ENST00000371953.8
PTEN	NM_001304717.5	c.649G>A	p.Gly217Ser	missense_variant	3/10
PTEN	NM_001304718.2	c.-576G>A		5_prime_UTR_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.130G>A	p.Gly44Ser	missense_variant	2/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PTEN hamartoma tumor syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 27, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 484604). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 44 of the PTEN protein (p.Gly44Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2020

The p.G44S variant (also known as c.130G>A), located in coding exon 2 of the PTEN gene, results from a G to A substitution at nucleotide position 130. The glycine at codon 44 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	0.82	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.75
Sift	Benign	0.049	D
Sift4G	Uncertain	0.054	T
Polyphen		0.98	D
Vest4		0.83
MutPred		0.45		Gain of phosphorylation at G44 (P = 0.1168);
MVP		0.96
MPC		1.9
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.84
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.24		Position offset: 34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554893812; hg19: chr10-89653832;