chr19-1220389-A-T

Variant names:

• chr19-1220389-A-T
• rs1131690938
• NM_000455.5:c.481A>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000455.5(STK11):​c.481A>T​(p.Ile161Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. I161L) has been classified as Uncertain significance.

• 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:1
• Conservation: PhyloP100: 1.32
• Publications: 2 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 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 29 uncertain in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-1220389-A-T is Pathogenic according to our data. Variant chr19-1220389-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 428774.

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.481A>T	p.Ile161Phe	missense	Exon 4 of 10	NP_000446.1
	STK11	NM_001407255.1		c.481A>T	p.Ile161Phe	missense	Exon 4 of 9	NP_001394184.1
	STK11	NR_176325.1		n.1748A>T		non_coding_transcript_exon	Exon 5 of 11

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.481A>T	p.Ile161Phe	missense	Exon 4 of 10	ENSP00000324856.6
	STK11	ENST00000652231.1		c.481A>T	p.Ile161Phe	missense	Exon 4 of 9	ENSP00000498804.1
	STK11	ENST00000585748.3	TSL:3	c.109A>T	p.Ile37Phe	missense	Exon 6 of 12	ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not provided (1)
1	-	-	Peutz-Jeghers syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.3
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.13	T
Polyphen		0.54	P
Vest4		0.88
MutPred		0.68		Loss of stability (P = 0.1151)
MVP		0.66
MPC		2.1
ClinPred		0.88	D
GERP RS		3.5
Varity_R		0.58
gMVP		0.78
Mutation Taster		=66/34	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1131690938; hg19: chr19-1220388; COSMIC: COSV58828738;