rs376280361

Variant names:

• chr19-1221997-G-A
• rs376280361
• NM_000455.5:c.911G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-1221997-G-A
• chr19-1221997-G-C
• chr19-1221997-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PM5 BS2

The NM_000455.5(STK11):​c.911G>A​(p.Arg304Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,570,750 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R304P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:1
• 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

Our verdict: Uncertain_significance. The variant received 0 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 NM_000455.5
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• BS2: High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.911G>A	p.Arg304Gln	missense_variant	Exon 7 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.911G>A	p.Arg304Gln	missense_variant	Exon 7 of 9		NP_001394184.1
STK11	NR_176325.1	n.2178G>A		non_coding_transcript_exon_variant	Exon 8 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.911G>A	p.Arg304Gln	missense_variant	Exon 7 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.911G>A	p.Arg304Gln	missense_variant	Exon 7 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.539G>A	p.Arg180Gln	missense_variant	Exon 9 of 12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152232 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD2 exomes AF: 0.0000387 AC: 7 AN: 180804 AF XY: 0.0000410

Gnomad AFR exome AF: 0.000103

Gnomad AMR exome AF: 0.0000361

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000184

Gnomad NFE exome AF: 0.0000131

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000176 AC: 25 AN: 1418518 Hom.: 0 Cov.: 30 AF XY: 0.0000142 AC XY: 10 AN XY: 701900

Gnomad4 AFR exome AF: 0.0000619 AC: 2 AN: 32308

Gnomad4 AMR exome AF: 0.0000258 AC: 1 AN: 38764

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25412

Gnomad4 EAS exome AF: 0.0000271 AC: 1 AN: 36948

Gnomad4 SAS exome AF: 0.0000124 AC: 1 AN: 80702

Gnomad4 FIN exome AF: 0.0000408 AC: 2 AN: 49000

Gnomad4 NFE exome AF: 0.0000156 AC: 17 AN: 1090950

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 58714

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152232 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74378

Gnomad4 AFR AF: 0.0000723 AC: 0.0000723415 AN: 0.0000723415

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.0000147007 AN: 0.0000147007

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.000256 AC: 1

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.0000258 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:3 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 304 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 7/180804 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same position, p.Arg304Trp and p.Arg304Pro, are known to be pathogenic (Clinvar variation ID: 183802, 428783), indicating that arginine at this position is important for STK11 function. Due to the lack of clinical data, 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. -

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2

Jul 19, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9809980, 17404884, 15121768, 12865922, 12552571, 10441497, 35264596, 15863673, 33471991) -

Hereditary cancer-predisposing syndrome Uncertain:2

Sep 27, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 304 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 7/180804 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same position, p.Arg304Trp and p.Arg304Pro, are known to be pathogenic (Clinvar variation ID: 183802, 428783), indicating that arginine at this position is important for STK11 function. Due to the lack of clinical data, 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. -

Feb 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R304Q variant (also known as c.911G>A), located in coding exon 7 of the STK11 gene, results from a G to A substitution at nucleotide position 911. The arginine at codon 304 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in breast cancer cohorts (Dorling et al. N Engl J Med. 2021 02;384:428-439; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). However, this variant has been identified in numerous individuals without features of PJS (Ambry Internal Data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peutz-Jeghers syndrome;C1336708:Germ cell tumor of testis;C1835047:Melanoma, cutaneous malignant, susceptibility to, 1;C2931038:Familial pancreatic carcinoma Uncertain:1

Jun 15, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

STK11-related disorder Uncertain:1

Sep 05, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The STK11 c.911G>A variant is predicted to result in the amino acid substitution p.Arg304Gln. This variant was reported in an individual with breast cancer and interpreted as uncertain (Table S3 Guindalini et al 2022. PubMed ID: 35264596). Two different missense change at the same amino acid position, c.910C>T (Arg304Trp) and c.911G>C (Arg304Pro), have been reported in patients with colon cancer and Peutz-Jeghers Syndrome (Resta et al. 1998. PubMed ID: 9809980; Boudeau et al. 2003. PubMed ID: 12552571; Mehenni et al. 2007. PubMed ID: 17404884, Aretz et al. 2005. PubMed ID: 16287113, Jiang et al. 2018. PubMed ID: 30092773). The c.911G>A variant is reported in 0.018% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-1221996-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.52	.;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	.;N
REVEL	Uncertain	0.57
Sift	Benign	0.18	.;T
Sift4G	Benign	0.15	T;T
Polyphen		0.96	.;D
Vest4		0.73
MVP		0.78
MPC		0.13
ClinPred		0.15	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.78
Mutation Taster		=46/54	disease causing

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; COSMIC: COSV109429977;