rs376702513

Variant names:

• chr10-87960876-C-T
• rs376702513
• NM_000314.8:c.802-18C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000314.8(PTEN):​c.802-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,299,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTEN NM_000314.8 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0610
• Publications: 2 publications found

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]

PTEN Gene-Disease associations (from GenCC):

• Cowden syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• PTEN hamartoma tumor syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• macrocephaly-autism syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• leiomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bannayan-Riley-Ruvalcaba syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lhermitte-Duclos disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Proteus-like syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glioma susceptibility 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-87960876-C-T is Benign according to our data. Variant chr10-87960876-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 92830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.802-18C>T		intron_variant	Intron 7 of 8	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1321-18C>T		intron_variant	Intron 8 of 9		NP_001291646.4
PTEN	NM_001304718.2	c.211-18C>T		intron_variant	Intron 7 of 8		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.802-18C>T		intron_variant	Intron 7 of 8	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes AF: 0.000416 AC: 52 AN: 125024 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000231

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000639

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00173

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000357

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00481 AC: 557 AN: 115828 AF XY: 0.00431

Gnomad AFR exome AF: 0.00358

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.00264

Gnomad EAS exome AF: 0.0172

Gnomad FIN exome AF: 0.000658

Gnomad NFE exome AF: 0.00525

Gnomad OTH exome AF: 0.00779

GnomAD4 exome AF: 0.00185 AC: 2409 AN: 1299150 Hom.: 0 Cov.: 30 AF XY: 0.00197 AC XY: 1276 AN XY: 646836

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00353 AC: 93 AN: 26354

American (AMR) AF: 0.00377 AC: 123 AN: 32634

Ashkenazi Jewish (ASJ) AF: 0.00324 AC: 76 AN: 23478

East Asian (EAS) AF: 0.00986 AC: 351 AN: 35612

South Asian (SAS) AF: 0.00398 AC: 283 AN: 71184

European-Finnish (FIN) AF: 0.000987 AC: 46 AN: 46604

Middle Eastern (MID) AF: 0.00263 AC: 13 AN: 4950

European-Non Finnish (NFE) AF: 0.00132 AC: 1329 AN: 1004716

Other (OTH) AF: 0.00177 AC: 95 AN: 53618

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000424 AC: 53 AN: 125022 Hom.: 0 Cov.: 28 AF XY: 0.000563 AC XY: 34 AN XY: 60384

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000441 AC: 14 AN: 31768

American (AMR) AF: 0.000231 AC: 3 AN: 12978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3068

East Asian (EAS) AF: 0.000641 AC: 3 AN: 4680

South Asian (SAS) AF: 0.00 AC: 0 AN: 4030

European-Finnish (FIN) AF: 0.00173 AC: 12 AN: 6928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 224

European-Non Finnish (NFE) AF: 0.000357 AC: 21 AN: 58808

Other (OTH) AF: 0.00 AC: 0 AN: 1724

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00143 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast and/or ovarian cancer Benign:1

Apr 23, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cowden syndrome 1 Benign:1

Feb 13, 2025

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

Hereditary cancer-predisposing syndrome Benign:1

Jan 21, 2016

Vantari Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.20
DANN	Benign	0.21
PhyloP100		0.061
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs376702513; hg19: chr10-89720633;