rs137853077

Positions:

• chr19-1207113-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000455.5(STK11):​c.200T>C​(p.Leu67Pro) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L67L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.74

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

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a region_of_interest Sufficient for interaction with SIRT1 (size 45) in uniprot entity STK11_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 19-1207113-T-C is Pathogenic according to our data. Variant chr19-1207113-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.200T>C	p.Leu67Pro	missense_variant	1/10	ENST00000326873.12
STK11	NM_001407255.1	c.200T>C	p.Leu67Pro	missense_variant	1/9
STK11	NR_176325.1	n.1336T>C		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.200T>C	p.Leu67Pro	missense_variant	1/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2020	This sequence change replaces leucine with proline at codon 67 of the STK11 protein (p.Leu67Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. 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.Leu67 amino acid residue in STK11. Other variant(s) that disrupt this residue have been observed in individuals with STK11-related conditions (PMID: 11389158), which suggests that this may be a clinically significant amino acid residue. This variant has been reported to affect STK11 protein function (PMID: 9837816, 10441497, 9887330, 15987703). This variant has been observed in individuals with clinical features of Peutz-Jeghers syndrome (PMID: 9428765, 15121768). ClinVar contains an entry for this variant (Variation ID: 7445). This variant is not present in population databases (ExAC no frequency). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 08, 1998	- -
Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	May 13, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 25, 2016	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2023	Published functional studies demonstrate a damaging effect: disrupted autophosphorylation of STK11 and absent kinase activity (Mehenni et al., 1998; Nezu et al., 1999; Ylikorkala et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16707622, 9428765, 11389158, 15121768, 29447078, 15863673, 15987703, 9887330, 10441497, 9837816) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 20, 2019	Not found in the total gnomAD dataset, and the data is high quality (0/272834 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 01, 2016

The p.L67P variant (also known as c.200T>C), located in coding exon 1 of the STK11 gene, results from a T to C substitution at nucleotide position 200. The leucine at codon 67 is replaced by proline, an amino acid with similar properties. This alteration was seen in multiple unrelated individuals meeting diagnostic criteria for Peutz-Jeghers syndrome (Hemminki A et al. Nature 1998 Jan;391(6663):184-7; Hearle N et al. Clin. Cancer Res. 2006 May;12(10):3209-15; Ambry internal data). This variant was previously reported in the SNPDatabase as rs137853077. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 125000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T;D;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.3	.;M;.
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.6	.;D;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	.;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.98
MutPred		0.84		Gain of disorder (P = 0.0312);Gain of disorder (P = 0.0312);Gain of disorder (P = 0.0312);
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		1.0
gMVP		0.95

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: rs137853077; hg19: chr19-1207112;