19-1226534-G-T

Variant names:

• chr19-1226534-G-T
• rs587780008
• NM_000455.5:c.1189G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000455.5(STK11):​c.1189G>T​(p.Ala397Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,607,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. A397L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: -0.764
• Publications: 3 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024791509).
• BP6: Variant 19-1226534-G-T is Benign according to our data. Variant chr19-1226534-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127699.
• BS2: High AC in GnomAdExome4 at 28 AD gene.

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.1189G>T	p.Ala397Ser	missense	Exon 9 of 10	NP_000446.1
	STK11	NR_176325.1		n.2456G>T		non_coding_transcript_exon	Exon 10 of 11

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.1189G>T	p.Ala397Ser	missense	Exon 9 of 10	ENSP00000324856.6
	STK11	ENST00000585748.3	TSL:3	c.817G>T	p.Ala273Ser	missense	Exon 11 of 12	ENSP00000477641.2
	STK11	ENST00000593219.6	TSL:3	n.*1014G>T		non_coding_transcript_exon	Exon 10 of 11	ENSP00000466610.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000430 AC: 1 AN: 232750 AF XY: 0.00000782

Gnomad AFR exome AF: 0.0000747

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1454910 Hom.: 0 Cov.: 31 AF XY: 0.0000207 AC XY: 15 AN XY: 723252

African (AFR) AF: 0.0000600 AC: 2 AN: 33352

American (AMR) AF: 0.00 AC: 0 AN: 44056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25928

East Asian (EAS) AF: 0.00 AC: 0 AN: 39456

South Asian (SAS) AF: 0.00 AC: 0 AN: 85160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1109782

Other (OTH) AF: 0.00 AC: 0 AN: 60010

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74378

African (AFR) AF: 0.0000241 AC: 1 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000151

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Feb 08, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The STK11 c.1189G>T (p.Ala397Ser) variant has been reported in the published literature in an individual with colorectal cancer (PMID: 28135145 (2017)). Additionally, a functional study suggests that the variant is not damaging to protein function (PMID: 34849607 (2021)). The frequency of this variant in the general population, 0.0000043 (1/232750 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

Nov 22, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate retained autophosphorylation activity (PMID: 34849607); Observed in an individual with colorectal cancer (PMID: 28135145); This variant is associated with the following publications: (PMID: 34849607, 28135145)

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The STK11 p.Ala397Ser variant was identified in 1 of 2116 proband chromosomes (frequency: 0.00047) from individuals or families with colorectal cancer (Yurgelun 2017). The variant was also identified in dbSNP (ID: rs587780008) as “With Uncertain significance allele”, in ClinVar (as likely benign by Ambry Genetics and uncertain significance by GeneDx and Invitae). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 1 of 229962 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following population: African in 1 of 13284 chromosomes (freq: 0.00008), while the variant was not observed in the Other, Latino, European (Non-Finnish), Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ala397 residue is not conserved in mammals and the variant amino acid Serine is present in dog and fruitfly, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

Peutz-Jeghers syndrome Uncertain:1 Benign:2

Sep 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:2

Sep 19, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 21, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

not specified Uncertain:1

May 30, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: STK11 c.1189G>T (p.Ala397Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-06 in 232750 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1189G>T has been reported in the literature in an individual affected with Colorectal Cancer, however authors classified the variant as VUS (Yurgelun_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (example: Donnelly_2021). The following publications have been ascertained in the context of this evaluation (PMID: 34849607, 28135145). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

Breast and/or ovarian cancer Uncertain:1

Jun 05, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.027
DANN	Benign	0.83
DEOGEN2	Benign	0.23	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-0.76
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.030
Sift	Benign	1.0	T
Sift4G	Benign	0.85	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.17		Gain of phosphorylation at A397 (P = 0.085)
MVP		0.31
MPC		0.039
ClinPred		0.12	T
GERP RS		-8.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.12
Mutation Taster		=94/6	polymorphism

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: rs587780008; hg19: chr19-1226533;