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 Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4 PP5

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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 stop_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 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: 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: Uncertain_significance. The variant received 5 ACMG points.

• 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 428265.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.1212A>C	p.Ter404Cysext*?	stop_lost	Exon 9 of 9	ENST00000371953.8	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

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.1212A>C	p.Ter404Cysext*?	stop_lost	Exon 9 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 20, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1212A>C variant (also known as p.*404CEXT*8), located in coding exon 9 of the PTEN gene, results from an A to C substitution at nucleotide position 1212, which is the last nucleotide of the PTEN gene. The stop codon at position 404 is replaced by Cysteine, resulting in an elongation of the protein by 8 amino acids. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data). In one study, a different but similar alteration, c.1211G>C, which replaces the stop codon at position 404 with a Serine and also results in the elongation of the protein by 8 amino acids was described; this alteration occurred de novo in a 3 year old male with macrocephaly, pervasive developmental disorder, hypotonia, frontal bossing, and enlarged perivascular spaces on neuroimaging (Vanderver A, et al. Am. J. Med. Genet. A 2014;164A(3):627-33). Another similar alteration, p.*404Cext*8 (c.1212A>T), has been confirmed de novo in a child with clinical features of PTEN hamartoma tumor syndrome (Ambry internal data, correspondence with external laboratory). In addition, 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). Additionally this variant has been confirmed as a de novo alteration (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

PTEN hamartoma tumor syndrome Uncertain:1

Jul 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change disrupts the translational stop signal of the PTEN mRNA. It is expected to extend the length of the PTEN protein by 8 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This protein extension has been observed in individual(s) with autism spectrum disorder (PMID: 31594918). ClinVar contains an entry for this variant (Variation ID: 428265). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

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	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;