rs786204940

Variant names:

• chr10-87863633-C-T
• rs786204940
• ENST00000692337.1:c.75C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The ENST00000692337.1(ENSG00000289051):​c.75C>T​(p.Ser25Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000485 in 391,412 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 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: ENSG00000289051 ENST00000692337.1 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:1
• Conservation: PhyloP100: 0.782

Genes affected

ENSG00000289051 (HGNC:55481):

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]

KLLN (HGNC:37212): (killin, p53 regulated DNA replication inhibitor) The protein encoded by this intronless gene is found in the nucleus, where it can inhibit DNA synthesis and promote S phase arrest coupled to apoptosis. The expression of this DNA binding protein is upregulated by transcription factor p53. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 10-87863633-C-T is Benign according to our data. Variant chr10-87863633-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 189497.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=0.782 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.-837C>T		5_prime_UTR_variant	Exon 1 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.-317C>T		5_prime_UTR_variant	Exon 1 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.-1542C>T		5_prime_UTR_variant	Exon 1 of 9		NP_001291647.1
KLLN	NM_001126049.2	c.-1146G>A		upstream_gene_variant		ENST00000445946.5	NP_001119521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000289051	ENST00000692337.1	c.75C>T	p.Ser25Ser	synonymous_variant	Exon 1 of 1			ENSP00000509326.1
PTEN	ENST00000371953	c.-837C>T		5_prime_UTR_variant	Exon 1 of 9	1	NM_000314.8	ENSP00000361021.3
KLLN	ENST00000445946.5	c.-1146G>A		upstream_gene_variant		6	NM_001126049.2	ENSP00000392204.2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000501 AC: 12 AN: 239332 Hom.: 0 Cov.: 0 AF XY: 0.0000493 AC XY: 6 AN XY: 121594

Gnomad4 AFR exome AF: 0.000294

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000443

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000587

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74296

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000529

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PTEN c.-837C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 4.6e-05 in 150856 control chromosomes (gnomAD v3.1.1). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-837C>T has been reported in the literature in a Cowden syndrome study (Nizialek_2015). This report does not provide unequivocal conclusions about association of the variant with Cowden Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters including an expert panel (ClinGen PTEN Variant Curation Expert Panel) (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Jun 18, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Describes a nucleotide substitution 837 basepairs upstream of the ATG translational start site in the PTEN promoter region; Observed in individuals with features of Cowden syndrome (PMID: 25669429); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.-836C>T; This variant is associated with the following publications: (PMID: 25669429) -

PTEN hamartoma tumor syndrome Benign:1

Oct 11, 2023

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

NM_000314.8(PTEN):c.-837C>T meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). BS1_P: To be applied for variants with filtering allele frequency of 0.0000043 up to 0.000043 (0.00043% up to 0.0043%) in gnomAD. Popmax FAF of this variant=0.00003249 [0.003249%] in gnomAD v3. BP5: Variant found in multiple cases with alternate molecular basis for disease. (internal laboratory contributor(s)) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Benign	0.97

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: rs786204940; hg19: chr10-89623390;