chr19-1218443-G-A

Position:

• chr19-1218443-G-A

Variant summary

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

The NM_000455.5(STK11):​c.317G>A​(p.Arg106Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,324 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 4.50

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]

STK11 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM1: In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 19 pathogenic changes around while only 5 benign (79%) in NM_000455.5
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.317G>A	p.Arg106Gln	missense_variant	2/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.317G>A	p.Arg106Gln	missense_variant	2/9		NP_001394184.1
STK11	NR_176325.1	n.1584G>A		non_coding_transcript_exon_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.317G>A	p.Arg106Gln	missense_variant	2/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.317G>A	p.Arg106Gln	missense_variant	2/9			ENSP00000498804.1
STK11	ENST00000585748	c.-56G>A		5_prime_UTR_variant	4/12	3		ENSP00000477641.2
STK11	ENST00000593219.5	n.*142G>A		non_coding_transcript_exon_variant	3/4	3		ENSP00000466610.1
STK11	ENST00000593219.5	n.*142G>A		3_prime_UTR_variant	3/4	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249170 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135222

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461324 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726928

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: 0.0000188

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

ESP6500AA AF: 0.000251 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces arginine with glutamine at codon 106 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 been identified in an individual affected with colorectal cancer (PMID: 32658311). This variant has been identified in 3/249170 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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 24, 2023	This missense variant replaces arginine with glutamine at codon 106 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 been identified in an individual affected with colorectal cancer (PMID: 32658311). This variant has been identified in 3/249170 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	Ambry Genetics	Aug 29, 2023	The p.R106Q variant (also known as c.317G>A), located in coding exon 2 of the STK11 gene, results from a G to A substitution at nucleotide position 317. The arginine at codon 106 is replaced by glutamine, an amino acid with highly similar properties. This alteration was seen in 0/732 breast cancer patients, 1/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 01;148:285-295). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2016

This variant is denoted STK11 c.317G>A at the cDNA level, p.Arg106Gln (R106Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Arg106Gln was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. STK11 Arg106Gln occurs at a position that is conserved in mammals and is located in the protein kinase domain (Uniprot). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether STK11 Arg106Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.086
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.085	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.50	.;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.73	.;N
REVEL	Benign	0.24
Sift	Benign	0.19	.;T
Sift4G	Benign	0.32	T;T
Polyphen		0.18	.;B
Vest4		0.38
MVP		0.54
MPC		1.1
ClinPred		0.14	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.22

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: rs375622587; hg19: chr19-1218442;