chr19-1221997-G-C

Position:

• chr19-1221997-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000326873.12(STK11):​c.911G>C​(p.Arg304Pro) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R304Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STK11 ENST00000326873.12 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.57

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.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in ENST00000326873.12
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1221996-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 19-1221997-G-C is Pathogenic according to our data. Variant chr19-1221997-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.911G>C	p.Arg304Pro	missense_variant	7/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.911G>C	p.Arg304Pro	missense_variant	7/9		NP_001394184.1
STK11	NR_176325.1	n.2178G>C		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.911G>C	p.Arg304Pro	missense_variant	7/10	1	NM_000455.5	ENSP00000324856	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1418520 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 701900

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.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 12, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10441497, 12552571]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16287113]. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 28, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg304 amino acid residue in STK11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9809980, 12865922, 15121768, 17404884). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STK11 protein function. ClinVar contains an entry for this variant (Variation ID: 428783). This missense change has been observed in individuals with clinical features of Peutz-Jeghers syndrome (PMID: 16287113, 30092773). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 304 of the STK11 protein (p.Arg304Pro). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 24, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30092773, 15863673, 35189935, 36033506, 16287113) -

STK11-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2024

The STK11 c.911G>C variant is predicted to result in the amino acid substitution p.Arg304Pro. This variant has been reported in individuals with Peutz-Jeghers syndrome (Aretz et al 2005. PubMed ID: 16287113; Jiang et al 2018. PubMed ID: 30092773). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic/likely pathogenic by multiple submitters in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/428783/). Another well characterized variant that disrupts this residue has been reported in individuals with Peutz-Jeghers syndrome (p.Arg304Trp) suggesting that variants that disrupt this residue are likely to be disease causing (Boudeau et al 2003. PubMed ID: 12552571; Resta et al 1998. PubMed ID: 9809980). This variant is interpreted as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2020

The p.R304P pathogenic mutation (also known as c.911G>C), located in coding exon 7 of the STK11 gene, results from a G to C substitution at nucleotide position 911. The arginine at codon 304 is replaced by proline, an amino acid with dissimilar properties. This pathogenic variant has been confirmed to be de novo in patients meeting clinical criteria for PJS as well as in several other families meeting clinical criteria for PJS where the variant segregated with disease (Aretz S et al. Hum. Mutat. 2005; 26:513-9: Jiang YL et al. BMC Med. Genet. 2018 08;19:141; Ambry internal data). In addition, a well characterized mutation affecting the same codon, STK11 p.R304W, has also been reported in patients with PJS (Boudeau J et al. Hum. Mutat. 2003 Feb; 21(2):172). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data; Resta N et al. Cancer Res. 1998 Nov; 58(21):4799-801). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.1	.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.4	.;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0030	.;D
Sift4G	Uncertain	0.046	D;D
Polyphen		1.0	.;D
Vest4		0.96
MutPred		0.87		Loss of catalytic residue at R304 (P = 0.0155);Loss of catalytic residue at R304 (P = 0.0155);
MVP		0.94
MPC		0.34
ClinPred		1.0	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.95

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: rs376280361; hg19: chr19-1221996;