10-87958018-A-G

Variant names:

• chr10-87958018-A-G
• rs1554825264
• NM_000314.8:c.800A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Strong

The NM_000314.8(PTEN):​c.800A>G​(p.Lys267Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. 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. K267?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-87958016-AAA-AC is described in Lovd as [Pathogenic].
• PP2: Missense variant in the PTEN gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 209 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 3.4883 (above the threshold of 3.09). Trascript score misZ: 4.1129 (above the threshold of 3.09). GenCC associations: The gene is linked to 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.800A>G	p.Lys267Arg	missense_variant, splice_region_variant	Exon 7 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1319A>G	p.Lys440Arg	missense_variant, splice_region_variant	Exon 8 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.209A>G	p.Lys70Arg	missense_variant, splice_region_variant	Exon 7 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.800A>G	p.Lys267Arg	missense_variant, splice_region_variant	Exon 7 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Mar 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 267 of the PTEN protein (p.Lys267Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 468716). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Nov 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K267R variant (also known as c.800A>G), located in coding exon 7 of the PTEN gene, results from an A to G substitution at nucleotide position 800. The lysine at codon 267 is replaced by arginine, an amino acid with highly similar properties. 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	Benign	0.12
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.50	D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.1	N;.
REVEL	Uncertain	0.38
Sift	Benign	0.089	T;.
Sift4G	Benign	0.12	T;T
Polyphen		0.046	B;.
Vest4		0.73
MutPred		0.43		Gain of sheet (P = 0.039);.;
MVP		0.85
MPC		1.2
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.39
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.010		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: rs1554825264; hg19: chr10-89717775;