rs1131690917

chr19-1207065-TGGG-Tchr19-1207065-TGGG-TGchr19-1207065-TGGG-TGGchr19-1207065-TGGG-TGGGG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_000455.5(STK11):c.155_157del(p.Gly52del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: STK11 NM_000455.5 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 9.65

Genes affected

STK11 (HGNC:11389): (serine/threonine kinase 11) The protein encoded by this gene is a serine/threonine kinase that regulates cell polarity and energy metabolism and functions as a tumor suppressor. Mutations in this gene have been associated with the autosomal dominant Peutz-Jeghers syndrome, as well as with skin, pancreatic, and testicular cancers. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a region_of_interest Sufficient for interaction with SIRT1 (size 45) in uniprot entity STK11_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000455.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 19-1207065-TGGG-T is Pathogenic according to our data. Variant chr19-1207065-TGGG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 428751.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.155_157del	p.Gly52del	inframe_deletion	1/10	ENST00000326873.12
STK11	NM_001407255.1	c.155_157del	p.Gly52del	inframe_deletion	1/9
STK11	NR_176325.1	n.1291_1293del		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.155_157del	p.Gly52del	inframe_deletion	1/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 03, 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: 428751). This variant is also known as 153del3. This variant has been observed in individual(s) with Peutz-Jeghers syndrome (PMID: 11389158). This variant is not present in population databases (gnomAD no frequency). This variant, c.155_157del, results in the deletion of 1 amino acid(s) of the STK11 protein (p.Gly52del), but otherwise preserves the integrity of the reading frame. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2015

The c.155_157delGGG variant (also known as p.G52del) is located in coding exon 1 of the STK11 gene. This variant results from an in-frame deletion of 3 nucleotides at positions 155 to 157, causing the removal of a highly conserved glycine residue at codon 52. This alteration, referred to as 153del3, was previously identified in one individual with a clinical diagnosis of Peutz-Jeghers syndrome (PJS), who was found to have perioral hyperpigmentation as well as hamartomatous lesions in the stomach, duodenum, and colon (Olschwang S et al. J. Med. Genet. 2001 Jun; 38(6):356-60). Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs1131690917; hg19: chr19-1207064;