19-1221332-T-C

Variant names:

• chr19-1221332-T-C
• rs1555738724
• NM_000455.5:c.854T>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000455.5(STK11):​c.854T>C​(p.Leu285Pro) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L285R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 6.08
• Publications: 0 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 38 uncertain in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1221332-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 628472.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 19-1221332-T-C is Pathogenic according to our data. Variant chr19-1221332-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 439305.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.854T>C	p.Leu285Pro	missense_variant	Exon 6 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.854T>C	p.Leu285Pro	missense_variant	Exon 6 of 9		NP_001394184.1
STK11	NR_176325.1	n.2121T>C		non_coding_transcript_exon_variant	Exon 7 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.854T>C	p.Leu285Pro	missense_variant	Exon 6 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.854T>C	p.Leu285Pro	missense_variant	Exon 6 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.482T>C	p.Leu161Pro	missense_variant	Exon 8 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*679T>C		non_coding_transcript_exon_variant	Exon 7 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6	n.*679T>C		3_prime_UTR_variant	Exon 7 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:1 Uncertain:1

Jun 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu285 amino acid residue in STK11. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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: 439305). This variant is also known as c.852T>C (p.L284P). This missense change has been observed in individual(s) with hamartomatous polyps and mucocutaneous pigmentation and/or STK11-related conditions (PMID: 17026623; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 285 of the STK11 protein (p.Leu285Pro). -

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 14, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L285P variant (also known as c.854T>C), located in coding exon 6 of the STK11 gene, results from a T to C substitution at nucleotide position 854. The leucine at codon 285 is replaced by proline, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with STK11-related disease (Ambry internal data). Based on internal structural analysis, this alteration is expected to destabilize the C-lobe of the kinase domain of the STK11 protein (Ambry internal data; Zeqiraj E et al. Science, 2009 Dec;326:1707-11). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified Uncertain:1

Feb 28, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.8	.;H
PhyloP100		6.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.6	.;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.99
MutPred		0.94		Loss of stability (P = 0.002);Loss of stability (P = 0.002);
MVP		0.93
MPC		0.35
ClinPred		1.0	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.99
gMVP		0.99
Mutation Taster		=1/99	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

Other links and lift over

dbSNP: rs1555738724; hg19: chr19-1221331;