NM_000314.8:c.253+1G>A

Variant names:

• chr10-87931090-G-A
• rs587776667
• NM_000314.8:c.253+1G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000314.8(PTEN):​c.253+1G>A variant causes a splice donor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 9.13

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 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7, offset of 4, new splice context is: tagGTatga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87931090-G-A is Pathogenic according to our data. Variant chr10-87931090-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87931090-G-A is described in Lovd as [Pathogenic]. Variant chr10-87931090-G-A is described in Lovd as [Likely_pathogenic]. Variant chr10-87931090-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.253+1G>A		splice_donor_variant, intron_variant	Intron 4 of 8	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.772+1G>A		splice_donor_variant, intron_variant	Intron 5 of 9		NP_001291646.4
PTEN	NM_001304718.2	c.-498+1G>A		splice_donor_variant, intron_variant	Intron 3 of 8		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.253+1G>A		splice_donor_variant, intron_variant	Intron 4 of 8	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00152 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cowden syndrome 1 Pathogenic:2

May 10, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 34386506, 28677221, 23470840, 29931205, 33723755]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 28677221]. -

May 26, 2017

Cancer Genomic Medicine Translational Research Lab, Cleveland Clinic Genomic Medicine Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

PTEN hamartoma tumor syndrome Pathogenic:2

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and dominant-negative are known mechanisms of disease in this gene and are associated with PTEN-related disease (OMIM). Loss of function has been associated with Cowden syndrome 1 (MIM#158350), Lhermitte-Duclos syndrome (MIM#158350) and macrocephaly/autism syndrome (MIM#605309) (PMID: 30311380). Dominant-negative has also been associated with missense variants associated with Cowden syndrome 1 and cancer (PMID: 24766807). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RNA studies have shown that this variant causes exon 4 skipping leading to a frameshift p.(Ala72Thrfs*5), that is predicted to cause nonsense mediated decay (PMID: 28677221). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0311 - An alternative nucleotide change at the same canonical splice site is present in gnomAD (v2, v3) (1 heterozygote, 0 homozygotes). (I) 0701 - Other NMD-predicted and canonical splice variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER, Clinvar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in more than five individuals with PTEN-related conditions (ClinVar, LOVD, PMID: 29931205, 21194675, 23470840). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 4 of the PTEN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of PTEN-related conditions (PMID: 9259288, 20600018, 21194675, 23470840). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7820). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Jan 12, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.253+1G>A splice site variant in the PTEN gene has been previously reported in at least two individuals with clinical features suggestive of PTEN-hamartoma tumor syndrome (Heald et al., 2010; Busch et al., 2013). This variant destroys the canonical splice donor site in intron 4, and is expected to cause abnormal gene splicing. Based on currently available evidence, we consider c.253+1G>A to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 29, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.253+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the PTEN gene. This mutation has been reported in individuals meeting clinical criteria for or suspected to have PTEN hamartoma tumor syndrome (Tan M et al. Am. J. Hum. Genet. 2011 Jan;88(1):42-56; Busch RM et al. Genet. Med. 2013 Jul;15(7):548-53; Nizialek E et al. Eur. J. Hum. Genet. 2015 Nov;23(11):1538-43). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Endometrial carcinoma Pathogenic:1

Aug 15, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Glioma susceptibility 2 Pathogenic:1

Jul 11, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Uncertain	0.90	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: 3
DS_DL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776667; hg19: chr10-89690847; COSMIC: COSV64289910;