rs1554897282

Positions:

• chr10-87925563-T-A
• chr10-87925563-T-C
• chr10-87925563-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_000314.8(PTEN):​c.209+6T>A variant causes a splice donor region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9913
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.13

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 10-87925563-T-A is Pathogenic according to our data. Variant chr10-87925563-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 2109004.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.209+6T>A		splice_donor_region_variant, intron_variant		ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.728+6T>A		splice_donor_region_variant, intron_variant			NP_001291646.4
PTEN	NM_001304718.2	c.-540-5483T>A		intron_variant			NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.209+6T>A		splice_donor_region_variant, intron_variant		1	NM_000314.8	ENSP00000361021	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 06, 2022

This sequence change falls in intron 3 of the PTEN gene. It does not directly change the encoded amino acid sequence of the PTEN protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PTEN protein in which other variant(s) (p.Tyr68His) have been determined to be pathogenic (PMID: 9467011, 9600246, 10866302, 19457929, 20926450, 25669429; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (Invitae). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.87		Position offset: -6

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-89685320; COSMIC: COSV64311421;