rs121913322

Positions:

• chr19-1221320-C-A
• chr19-1221320-C-G
• chr19-1221320-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_000455.5(STK11):​c.842C>A​(p.Pro281Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,609,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P281L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• Conservation: PhyloP100: 5.87

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_benign. Variant got -4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 uncertain in NM_000455.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.21615165).
• BS2: High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.842C>A	p.Pro281Gln	missense_variant	6/10	ENST00000326873.12
STK11	NM_001407255.1	c.842C>A	p.Pro281Gln	missense_variant	6/9
STK11	NR_176325.1	n.2109C>A		non_coding_transcript_exon_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.842C>A	p.Pro281Gln	missense_variant	6/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000291 AC: 7 AN: 240870 Hom.: 0 AF XY: 0.0000152 AC XY: 2 AN XY: 131162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000887

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000568

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000277

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000172 AC: 25 AN: 1457030 Hom.: 0 Cov.: 31 AF XY: 0.0000152 AC XY: 11 AN XY: 724426

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000677

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: 0.0000171

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00000876 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000416 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15863673, 37125020) -
Uncertain significance, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 18, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 15, 2019	The STK11 c.842C>A; p.Pro281Gln variant (rs121913322), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 127705). This variant is found in the general population with an overall allele frequency of 0.003% (7/240870 alleles) in the Genome Aggregation Database. The proline at codon 281 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of this variant is uncertain at this time. -

Peutz-Jeghers syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces proline with glutamine at codon 281 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with STK11-related disorders in the literature. This variant has been identified in 7/240870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 08, 2023	This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 281 of the STK11 protein (p.Pro281Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 127705). 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 not expected to disrupt STK11 protein function with a negative predictive value of 95%. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 10, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 15, 2023	This missense variant replaces proline with glutamine at codon 281 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with STK11-related disorders in the literature. This variant has been identified in 7/240870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Carcinoma of pancreas Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 27, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.78
DEOGEN2	Benign	0.25	T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.017
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
Sift4G	Benign	0.61	T;T
Polyphen		0.12	.;B
Vest4		0.56
MVP		0.32
MPC		0.046
ClinPred		0.13	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.17
gMVP		0.44

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: rs121913322; hg19: chr19-1221319;