rs876660879

chr10-87965472-A-Cchr10-87965472-A-Gchr10-87965472-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000314.8(PTEN):c.1212A>C(p.Ter404CysextTer8) 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
• Conservation: PhyloP100: 8.90

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 submissions are: {Uncertain_significance=1, Pathogenic=1}.
• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.105787).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.1212A>C	p.Ter404CysextTer8	stop_lost	9/9	ENST00000371953.8
PTEN	NM_001304717.5	c.1731A>C	p.Ter577CysextTer8	stop_lost	10/10
PTEN	NM_001304718.2	c.621A>C	p.Ter207CysextTer8	stop_lost	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.1212A>C	p.Ter404CysextTer8	stop_lost	9/9	1	NM_000314.8	P1

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2022

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 21, 2022

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 428265). This protein extension has been observed in individual(s) with autism spectrum disorder (PMID: 31594918). This variant is not present in population databases (gnomAD no frequency). 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. -

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
MutationTaster	Benign	1.0	N
Vest4		0.23
GERP RS		4.2

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

Publications

LitVar

Other links and lift over

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