19-1219356-T-C

Variant names:

• chr19-1219356-T-C
• rs1060499958
• NM_000455.5:c.407T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000455.5(STK11):​c.407T>C​(p.Met136Thr) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 7.78

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 19 pathogenic changes around while only 5 benign (79%) in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• PP5: Variant 19-1219356-T-C is Pathogenic according to our data. Variant chr19-1219356-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 403772.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.407T>C	p.Met136Thr	missense_variant	Exon 3 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.407T>C	p.Met136Thr	missense_variant	Exon 3 of 9		NP_001394184.1
STK11	NR_176325.1	n.1674T>C		non_coding_transcript_exon_variant	Exon 4 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.407T>C	p.Met136Thr	missense_variant	Exon 3 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.407T>C	p.Met136Thr	missense_variant	Exon 3 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.35T>C	p.Met12Thr	missense_variant	Exon 5 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.5	n.*232T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 4	3		ENSP00000466610.1
STK11	ENST00000593219.5	n.*232T>C		3_prime_UTR_variant	Exon 4 of 4	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1430342 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 709864

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:2 Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 403772). This missense change has been observed in individuals with clinical features of Peutz-Jeghers syndrome (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 136 of the STK11 protein (p.Met136Thr). -

Dec 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: STK11 c.407T>C (p.Met136Thr) results in a non-conservative amino acid change located in the Protein Kinase Domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Other variants at the same amino acid position have been reported in the literature in indivduals with Peutz-Jeghers Syndrome (M136K, M136R; Tchekmedyian_2013, Olschwang_2001). The variant was absent in 225652 control chromosomes. c.407T>C has been observed in multiple individuals affected with a personal and family history of Peutz-Jeghers Syndrome at our laboratory (internal data). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 403772). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Jan 03, 2019

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The M136T variant in the STK11 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M136T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and is located within the site of catalysis (Hearle et al., 2006). In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (M136K, M136R) have been reported in association with Peutz-Jeghers syndrome, supporting the functional importance of this region of the protein (Olschwang et al., 2001; Tchekmedyian et al., 2013). Based on the currently available information, M136T is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 03, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M136T variant (also known as c.407T>C), located in coding exon 3 of the STK11 gene, results from a T to C substitution at nucleotide position 407. The methionine at codon 136 is replaced by threonine, an amino acid with similar properties. This variant has been observed in multiple individuals with a personal and/or family history that is consistent with Peutz-Jeghers syndrome (External communication, Ambry internal data). Based on internal structural analysis, M136T is mildly destabilizing to the local structure and more destabilizing than a nearby pathogenic variant (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.95
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	T;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	-0.0050	.;.;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.5	.;.;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	.;.;D
Sift4G	Uncertain	0.0050	.;D;D
Polyphen		0.74	.;.;P
Vest4		0.92, 0.92
MutPred		0.77		.;Gain of phosphorylation at M136 (P = 0.2215);Gain of phosphorylation at M136 (P = 0.2215);
MVP		0.92
MPC		2.2
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.8
Varity_R		0.82
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1060499958; hg19: chr19-1219355;