19-1221332-T-G

Variant names:

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

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>G​(p.Leu285Arg) 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. L285P) 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:1 U:1
• 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-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 439305.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 19-1221332-T-G is Pathogenic according to our data. Variant chr19-1221332-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 628472.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.854T>G	p.Leu285Arg	missense_variant	Exon 6 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.854T>G	p.Leu285Arg	missense_variant	Exon 6 of 9		NP_001394184.1
STK11	NR_176325.1	n.2121T>G		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>G	p.Leu285Arg	missense_variant	Exon 6 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.854T>G	p.Leu285Arg	missense_variant	Exon 6 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.482T>G	p.Leu161Arg	missense_variant	Exon 8 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*679T>G		non_coding_transcript_exon_variant	Exon 7 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6	n.*679T>G		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:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:1

Oct 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 285 of the STK11 protein (p.Leu285Arg). 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 observed in individuals with STK11-related conditions (PMID: 17026623, 26430231; Invitae), which suggests that this may be a clinically significant amino acid residue. 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: 628472). This missense change has been observed in individual(s) with Peutz-Jeghers syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). -

Hereditary cancer-predisposing syndrome Uncertain:1

Apr 09, 2019

Color Diagnostics, LLC DBA Color Health

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	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.8	.;H
PhyloP100		6.1
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.6	.;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.040	D;D
Polyphen		1.0	.;D
Vest4		0.99
MutPred		0.89		Loss of stability (P = 0.0059);Loss of stability (P = 0.0059);
MVP		0.91
MPC		0.34
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.99
gMVP		0.99
Mutation Taster		=2/98	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; COSMIC: COSV58827781;