rs587780009

Variant names:

• chr19-1220369-G-A
• rs587780009
• NM_000455.5:c.465-4G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-1220369-G-A
• chr19-1220369-G-C
• chr19-1220369-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000455.5(STK11):​c.465-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,598,454 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000062 (1 hom.)
• Consequence: STK11 NM_000455.5 splice_region, intron
• Scores: Splicing: ADA: 0.00005752
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:14
• Conservation: PhyloP100: -0.575
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-1220369-G-A is Benign according to our data. Variant chr19-1220369-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127703.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000615 (89/1446234) while in subpopulation SAS AF = 0.00037 (31/83784). AF 95% confidence interval is 0.000267. There are 1 homozygotes in GnomAdExome4. There are 57 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 89 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.465-4G>A		splice_region_variant, intron_variant	Intron 3 of 9	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.465-4G>A		splice_region_variant, intron_variant	Intron 3 of 8		NP_001394184.1
STK11	NR_176325.1	n.1732-4G>A		splice_region_variant, intron_variant	Intron 4 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.465-4G>A		splice_region_variant, intron_variant	Intron 3 of 9	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.465-4G>A		splice_region_variant, intron_variant	Intron 3 of 8			ENSP00000498804.1
STK11	ENST00000585748.3	c.93-4G>A		splice_region_variant, intron_variant	Intron 5 of 11	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*290-4G>A		splice_region_variant, intron_variant	Intron 4 of 10	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152220 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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000850 AC: 19 AN: 223438 AF XY: 0.0000988

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000125

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000199

Gnomad OTH exome AF: 0.000180

GnomAD4 exome AF: 0.0000615 AC: 89 AN: 1446234 Hom.: 1 Cov.: 32 AF XY: 0.0000794 AC XY: 57 AN XY: 718004

African (AFR) AF: 0.0000601 AC: 2 AN: 33280

American (AMR) AF: 0.000118 AC: 5 AN: 42510

Ashkenazi Jewish (ASJ) AF: 0.0000388 AC: 1 AN: 25746

East Asian (EAS) AF: 0.00 AC: 0 AN: 39118

South Asian (SAS) AF: 0.000370 AC: 31 AN: 83784

European-Finnish (FIN) AF: 0.0000196 AC: 1 AN: 51074

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5742

European-Non Finnish (NFE) AF: 0.0000389 AC: 43 AN: 1105176

Other (OTH) AF: 0.0000669 AC: 4 AN: 59804

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74356

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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: 10620

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.0000491

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:2 Benign:4

Jan 26, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 24, 2014

Pathway Genomics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 14, 2023

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:4

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 13, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: STK11 c.465-4G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing. The variant allele was found at a frequency of 8.5e-05 in 223438 control chromosomes, predominantly at a frequency of 0.0004 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 64 fold of the estimated maximal estimated allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.465-4G>A has been reported in the literature in one individual affected with Peutz-Jeghers Syndrome (Aretz_2005), however authors are unclear about the possible splice impact. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Thirteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified as Benign (n=1), Likely Benign (n=7) and VUS (n=5). Based on the evidence outlined above, the variant was classified as likely benign. -

Dec 15, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This is a splice variant in intron 3 of STK11 (10 total exons). The variant has been reported in one individual with Peutz Jeghers (Aretz 2005). This variant is has a Max MAF of 0.07% in ExAC (7 South Asian alleles) and 0.04% in gnomAD (12 South Asian alleles). Classified as Likely benign by 3 submitters (GeneDx, Ambry, Invitae) and VUS by Pathway Genomics. -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4

Apr 22, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 16, 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. -

Apr 12, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided Uncertain:1 Benign:1

Mar 22, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16287113, 28873162) -

Sep 01, 2017

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Uncertain:1

Jan 17, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast carcinoma Uncertain:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The STK11 c.465-4G>A variant was identified in 1 of 142 proband chromosomes (frequency: 0.007) from individuals or families with Peutz-Jeghers syndrome (Aretz 2005). The variant was also identified in the following databases: dbSNP (ID: rs587780009) as "With other allele", ClinVar (2x uncertain significance, 3x likely benign), Clinvitae, and the Zhejiang Colon Cancer Database (1x). The variant was not identified in Cosmic, MutDB, LOVD 3.0, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 19 of 220968 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include other in 1 of 5028 chromosomes (freq: 0.0002), Latino in 4 of 31136 chromosomes (freq: 0.0001), European in 2 of 99398 chromosomes (freq: 0.00002), Ashkenazi Jewish in 1 of 9228 chromosomes (freq: 0.0001), and South Asian in 11 of 27928 chromosomes (freq: 0.0004). The variant was not observed in the African, East Asian, or Finnish populations. The identification of this variant together with a co-occurring pathogenic variant in the PALB2 gene (c.661_662delinsTA, p.Val221X) by our laboratory in one individual with breast cancer increases the likelihood this variant does not have clinical significance. The c.465-4G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions nor at positions -3 and -5 to -12 which are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.1
DANN	Benign	0.83
PhyloP100		-0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000058
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.020		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: rs587780009; hg19: chr19-1220368;