NM_000455.5:c.608C>G

Variant names:

• chr19-1220591-C-G
• rs587782379
• NM_000455.5:c.608C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000455.5(STK11):​c.608C>G​(p.Pro203Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P203L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.07
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• familial pancreatic carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Peutz-Jeghers syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Genomics England PanelApp, G2P
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000455.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	NM_000455.5	MANE Select	c.608C>G	p.Pro203Arg	missense	Exon 5 of 10	NP_000446.1
	STK11	NM_001407255.1		c.608C>G	p.Pro203Arg	missense	Exon 5 of 9	NP_001394184.1
	STK11	NR_176325.1		n.1875C>G		non_coding_transcript_exon	Exon 6 of 11

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.608C>G	p.Pro203Arg	missense	Exon 5 of 10	ENSP00000324856.6
	STK11	ENST00000652231.1		c.608C>G	p.Pro203Arg	missense	Exon 5 of 9	ENSP00000498804.1
	STK11	ENST00000585748.3	TSL:3	c.236C>G	p.Pro79Arg	missense	Exon 7 of 12	ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Aug 27, 2015

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P203R variant (also known as c.608C>G), located in coding exon 5 of the STK11 gene, results from a C to G substitution at nucleotide position 608. The proline at codon 203 is replaced by arginine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5994 samples (11988 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 110000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of p.P203R remains unclear.

Peutz-Jeghers syndrome Uncertain:1

Apr 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant has not been reported in the literature in individuals with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 233612). This sequence change replaces proline with arginine at codon 203 of the STK11 protein (p.Pro203Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Benign	0.77
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.051
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.74	N
PhyloP100		6.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.45
Sift	Benign	0.36	T
Sift4G	Benign	0.70	T
Polyphen		0.022	B
Vest4		0.78
MutPred		0.38		Gain of solvent accessibility (P = 0.0411)
MVP		0.76
MPC		1.1
ClinPred		0.56	D
GERP RS		5.6
Varity_R		0.49
gMVP		0.91
Mutation Taster		=52/48	polymorphism

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

Other links and lift over

dbSNP: rs587782379; hg19: chr19-1220590; COSMIC: COSV109430050;