rs876660879

Variant names:

• chr10-87965472-A-C
• rs876660879
• NM_000314.8:c.1212A>C

Your query was ambiguous. Multiple possible variants found:

• chr10-87965472-A-C
• chr10-87965472-A-G
• chr10-87965472-A-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PM4 PP5_Very_Strong

The NM_000314.8(PTEN):​c.1212A>C​(p.Ter404Cysext*?) variant causes a stop lost change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000580060: Functional assays for a similar alteration, p.*404LEXT*8 (also known as X404L), which replaces the stop codon at position 404 with a Leucine, and also results in the elongation of the protein by 8 amino acids, demonstrated this alteration was unable to rescue abnormal morphogenesis in cells depleted of PTEN (Berglund FM, et al. Oncogene 2013 Sep" and additional evidence is available in ClinVar. The gene PTEN is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 stop_lost
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:1 O:1
• Conservation: PhyloP100: 8.90
• Publications: 1 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: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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

Specifications for PTEN are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000580060: Functional assays for a similar alteration, p.*404LEXT*8 (also known as X404L), which replaces the stop codon at position 404 with a Leucine, and also results in the elongation of the protein by 8 amino acids, demonstrated this alteration was unable to rescue abnormal morphogenesis in cells depleted of PTEN (Berglund FM, et al. Oncogene 2013 Sep; 32(37):4417-26).
• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_000314.8 Downstream stopcodon found after 684 codons.
• PP5: Variant 10-87965472-A-C is Pathogenic according to our data. Variant chr10-87965472-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 428265.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000314.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	NM_000314.8	MANE Select	c.1212A>C	p.Ter404Cysext*?	stop_lost	Exon 9 of 9	NP_000305.3
	PTEN	NM_001304717.5		c.1731A>C	p.Ter577Cysext*?	stop_lost	Exon 10 of 10	NP_001291646.4
	PTEN	NM_001304718.2		c.621A>C	p.Ter207Cysext*?	stop_lost	Exon 9 of 9	NP_001291647.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	ENST00000371953.8	TSL:1 MANE Select	c.1212A>C	p.Ter404Cysext*?	stop_lost	Exon 9 of 9	ENSP00000361021.3	P60484-1
	PTEN	ENST00000693560.1		c.1731A>C	p.Ter577Cysext*?	stop_lost	Exon 10 of 10	ENSP00000509861.1	A0A8I5KSF9
	PTEN	ENST00000700029.2		c.1305A>C	p.Ter435Cysext*?	stop_lost	Exon 10 of 10	ENSP00000514759.2	A0A8V8TPK6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	PTEN hamartoma tumor syndrome (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.69
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		8.9
Vest4		0.23
GERP RS		4.2
Mutation Taster		=6/194	disease causing (ClinVar)

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: rs876660879; hg19: chr10-89725229; COSMIC: COSV64310338; COSMIC: COSV64310338;