rs587781681

Positions:

• chr19-1219418-G-A
• chr19-1219418-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PP3_Strong BP6 BS2

The NM_000455.5(STK11):​c.464+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000209 in 1,576,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: STK11 NM_000455.5 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:3
• Conservation: PhyloP100: 9.05

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_benign. Variant got -1 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 19-1219418-G-A is Benign according to our data. Variant chr19-1219418-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141354.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=8}.
• BS2: High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.464+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.464+5G>A		splice_donor_5th_base_variant, intron_variant			NP_001394184.1
STK11	NR_176325.1	n.1731+5G>A		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.464+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_000455.5	ENSP00000324856	P1

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 150476 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000491

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: 0.0000957

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000213 AC: 4 AN: 187980 Hom.: 0 AF XY: 0.0000198 AC XY: 2 AN XY: 101206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000497

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000210 AC: 30 AN: 1425544 Hom.: 0 Cov.: 51 AF XY: 0.0000198 AC XY: 14 AN XY: 705680

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000393

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000492

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000228

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 150476 Hom.: 0 Cov.: 34 AF XY: 0.0000136 AC XY: 1 AN XY: 73340

Gnomad4 AFR AF: 0.0000491

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000957

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000502 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 09, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 17, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2023	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 15863673) -

Peutz-Jeghers syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 22, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 18, 2023	This variant causes a G to A nucleotide substitution at the +5 position of intron 3 of the STK11 gene. Splice site prediction tools predict that this variant may impact RNA splicing, although this prediction has not been confirmed in published RNA studies. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/218862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Peutz-Jeghers syndrome;C0153594:Malignant tumor of testis;C0235974:Carcinoma of pancreas Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 03, 2023

- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The STK11 c.464+5G>A variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, Zhejiang University Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs587781681) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae and Color Genomics Inc.), Clinvitae (3x), and in control databases in 5 of 213708 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population includes European Non-Finnish in 5 of 93184 chromosomes (freq: 0.00005) while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant was identified in a case along with a co-occurring pathogenic variant in BRCA2 (c.9097dupA, p.Thr3033AsnfsX11). The c.464+5G>A variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Mar 19, 2024

Variant summary: STK11 c.464+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.1e-05 in 1576020 control chromosomes. The observed variant frequency is approximately 3.35 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is benign. c.464+5G>A has been reported in the literature as a VUS in settings of multigene panel testing in an individual with a personal and family history of Breast and/or Colorectal cancer (example, de Oliveira_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35534704). ClinVar contains an entry for this variant (Variation ID: 141354). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	13
DANN	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.82		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587781681; hg19: chr19-1219417;