rs876661012

chr19-1207091-T-TAchr19-1207091-T-TAA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000455.5(STK11):c.179dup(p.Tyr60Ter) variant causes a stop gained, frameshift 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y60Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: STK11 NM_000455.5 stop_gained, frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.00

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-1207091-T-TA is Pathogenic according to our data. Variant chr19-1207091-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 234416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.179dup	p.Tyr60Ter	stop_gained, frameshift_variant	1/10	ENST00000326873.12
STK11	NM_001407255.1	c.179dup	p.Tyr60Ter	stop_gained, frameshift_variant	1/9
STK11	NR_176325.1	n.1315dup		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.179dup	p.Tyr60Ter	stop_gained, frameshift_variant	1/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2018	This duplication of one nucleotide is denoted STK11 c.179dupA at the cDNA level and p.Tyr60Ter (Y60X) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TCTT[dupA]CGGC. The duplication creates a nonsense variant, which changes a Tyrosine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. STK11 c.179dupA has been observed in individuals reported as having Peutz-Jeghers syndrome (Aretz 2005, Salloch 2010, Wang 2014). Additionally, the adjacent variants STK11 c.180C>G and c.180C>A, which also result in a premature stop codon at this residue (p.Tyr60Ter), have been reported in several individuals meeting clinical diagnostic criteria for Peutz-Jeghers syndrome (Wang 1999, Olschwang 2001, Lim 2003, Zhao 2012, Li 2017). We therefore consider STK11 c.179dupA to be pathogenic. -

Peutz-Jeghers syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

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: rs876661012; hg19: chr19-1207090;