19-1220488-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000455.5(STK11):c.580G>T(p.Asp194Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D194E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.86

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 12 ACMG points.

• PM1: In a mutagenesis_site Loss of kinase activity. (size 0) in uniprot entity STK11_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1220490-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 19-1220488-G-T is Pathogenic according to our data. Variant chr19-1220488-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 7450.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.580G>T	p.Asp194Tyr	missense_variant	4/10	ENST00000326873.12
STK11	NM_001407255.1	c.580G>T	p.Asp194Tyr	missense_variant	4/9
STK11	NR_176325.1	n.1847G>T		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.580G>T	p.Asp194Tyr	missense_variant	4/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1453080 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722078

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Melanoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2020

The p.D194Y pathogenic mutation (also known as c.580G>T), located in coding exon 4 of the STK11 gene, results from a G to T substitution at nucleotide position 580. The aspartic acid at codon 194 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in an individual with a clinical diagnosis of Peutz-Jeghers syndrome (PJS) (Zheng B et al. J Pediatr Gastroenterol Nutr, 2017 04;64:559-564). Two other alterations at the same codon, p.D194N (c.580G>A) and p.D194E (c.582C>A), have been described in multiple families meeting clinical diagnostic criteria for PJS (Westerman AM et al. Hum. Mutat. 1999;13:476-81; Lim W et al. Br. J. Cancer. 2003 Jul;89:308-13; Schumacher V et al. J. Med. Genet. 2005 May;42:428-35; Hearle NC et al. J. Med. Genet. 2006 Apr;43:e15; Chow E et al. Clin. Genet. 2006 Nov;70:409-14; Klumpen, HJ et al. J Clin Oncol. 2011 Feb 20;29(6):e150-3; Korsse, SE et al. J Med Genet. 2013 Jan;50(1):59-64; Borun P et al. BMC Med. Genet. 2013 May;14:58; Jiang YL et al. Cancer Genet. 2019 01;230:47-57). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In one functional study, this alteration demonstrated reduced kinase activity compared to wildtype (Granado-Martínez P et al. Commun Biol, 2020 Jul;3:366). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Melanoma, cutaneous malignant, susceptibility to, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 04, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;D;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		1.0
MutPred		0.95		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP		0.99
MPC		2.4
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0

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: rs121913315; hg19: chr19-1220487; COSMIC: COSV58820621; COSMIC: COSV58820621;