NM_000455.5:c.1226G>A

STK11 · NP_000446.1:p.(Arg409Gln) · NM_000455.5

GRCh37: chr19:1226570 G>A · GRCh38: chr19:1226571 G>A

Gene: STK11 Transcript: NM_000455.5

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

STK11

Transcript

NM_000455.5

Protein

NP_000446.1:p.(Arg409Gln)

gnomAD AF

3.276036298482187e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000455.5:c.1226G>A (p.Arg409Gln) is a missense variant in STK11, a gene associated with autosomal dominant Peutz-Jeghers syndrome.

This variant is present at extremely low frequency in population databases: gnomAD v2.1 allele frequency 0.0036% (7/193,536 alleles) and gnomAD v4.1 allele frequency 0.0033% (52/1,587,284 alleles), with no homozygotes observed. PM2 (supporting) is met.

Multiple computational prediction tools suggest a benign effect: REVEL score 0.122, BayesDel score -0.514, and SpliceAI max delta 0.00. BP4 (supporting) is met.

A same-residue variant, p.Arg409Trp (R409W), was evaluated in a functional study (PMID:34849607) and was found to retain WT-like kinase activity and p53-mediated transcriptional activation, suggesting that amino acid substitution at this position may not disrupt STK11 function.

The variant has been reported in ClinVar predominantly as a variant of uncertain significance (11 clinical laboratories), with 2 laboratories classifying as likely benign and 1 as benign. No expert panel review is available.

This variant is observed in COSMIC in somatic cancers at low frequency (n=1), which does not provide evidence for germline pathogenicity.

No variant-specific publications were identified in the reviewed literature. PMID:34849607 evaluated R409W at the same residue but did not directly study R409Q.

Applying generic ACMG/AMP 2015 classification rules: one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met. These offset each other, resulting in an overall classification of Uncertain Significance.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_000455.5:c.1226G>A is a missense variant (p.Arg409Gln) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable.	pvs1_variant_assessment
PS1	Not met	No known pathogenic variant has been reported at the same nucleotide position (c.1226G>A) with the same amino acid change. No evidence from ClinVar, COSMIC, or literature supports a PS1-level prior.	clinvar
PS2	Not met	No de novo occurrence of NM_000455.5:c.1226G>A was identified in any reviewed publication or ClinVar submission. No parentage-confirmed de novo report available.
PS3	Not met	No well-established functional study directly assessing NM_000455.5:c.1226G>A (p.Arg409Gln) was identified. PMID:34849607 evaluated the same-residue variant p.Arg409Trp and found it retained WT-like kinase activity and p53-mediated transcriptional activation, but this does not constitute direct functional evidence for p.Arg409Gln.	PMID:34849607
PS4	Not met	No case-control study demonstrates statistically significant enrichment of NM_000455.5:c.1226G>A in affected individuals versus controls. The variant has been observed in gnomAD population databases at low frequency (0.0036%), which does not support a PS4 argument.	gnomad_v2 gnomad_v4
PS5	Not met	No evidence that NM_000455.5:c.1226G>A has been identified in a case where an alternate molecular cause of disease was established. No data to support this criterion.
PM1	Not met	The variant does not lie in a statistically significant mutational hotspot in STK11. Hotspot analysis of the residue (R409) did not identify significant clustering of pathogenic variants.
PM2	Met	NM_000455.5:c.1226G>A is present in gnomAD v2.1 at an allele frequency of 0.0036% (7/193,536 alleles, 0 homozygotes) and in gnomAD v4.1 at 0.0033% (52/1,587,284 alleles, 0 homozygotes), well below the 0.1% threshold for PM2 at supporting level. Absent from gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	PM5 candidate harvesting did not identify a confirmed pathogenic missense variant at the same residue (R409) suitable as a comparator. R409W was evaluated in PMID:34849607 and found to retain WT-like kinase and transcriptional activity, precluding its use as a pathogenic comparator for PM5.	pm5_candidates PMID:34849607
PM6	Not met	No confirmed de novo occurrence of NM_000455.5:c.1226G>A has been reported. PM6 requires a de novo observation with confirmed maternity and paternity, which is not available.
PP1	Not met	No segregation data are available for NM_000455.5:c.1226G>A. No family studies demonstrating co-segregation with disease have been published.
PP2	Not met	PP2 applies when a missense variant occurs in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease. STK11 has a significant number of benign missense variants reported and the specific variant has been observed in population databases, so PP2 is not met.	gnomad_v2 gnomad_v4
PP3	Not met	Multiple lines of computational evidence suggest a benign effect rather than a deleterious effect. REVEL score is 0.122 (well below typical pathogenic threshold of >0.5), BayesDel score is -0.514 (strongly in the benign range), and SpliceAI predicts no splicing impact (max delta = 0.00). These results are discordant with a PP3 determination.	revel bayesdel spliceai
PP4	Not met	No detailed phenotypic data specific to individuals carrying NM_000455.5:c.1226G>A are available. PP4 requires that the variant be identified in a patient with a phenotype highly specific for the gene/disease, which cannot be assessed.
PP5	Not met	No reputable source (expert panel, professional practice guideline, or clinical diagnostic laboratory with comprehensive evidence) classifies NM_000455.5:c.1226G>A as pathogenic. ClinVar classification is VUS (11 labs) with minority likely benign/benign (3 labs); no expert panel review exists.	clinvar
BA1	Not met	The variant allele frequency in gnomAD (0.0036% v2.1, 0.0033% v4.1) is far below the BA1 threshold of >1% in any population. BA1 is not met.	gnomad_v2 gnomad_v4
BS1	Not met	The variant allele frequency in gnomAD (0.0036% v2.1, 0.0033% v4.1) is well below the BS1 threshold of >0.3% in any population. BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observations of NM_000455.5:c.1226G>A have been reported in any population database. BS2 requires observation in a healthy adult individual in trans with a pathogenic variant or in a homozygous state, which is not available.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional study directly demonstrates that NM_000455.5:c.1226G>A (p.Arg409Gln) has no deleterious effect. A same-residue variant (p.Arg409Trp) was shown to retain WT-like function in PMID:34849607, but this indirect evidence alone is insufficient to meet BS3 without direct testing of p.Arg409Gln.	PMID:34849607
BS4	Not met	No segregation data are available to demonstrate lack of co-segregation with disease. BS4 requires non-segregation evidence, which has not been reported for this variant.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where only truncating variants cause disease. STK11 is associated with Peutz-Jeghers syndrome through both missense and truncating pathogenic variants; therefore BP1 does not apply.	pvs1_gene_context
BP2	Not met	No observation of NM_000455.5:c.1226G>A occurring in trans with a known pathogenic STK11 variant has been reported. BP2 requires co-occurrence data that is not available.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.122 (well below the 0.5 pathogenic cutoff), BayesDel score is -0.514 (strongly in the benign range), and SpliceAI predicts no aberrant splicing (max delta = 0.00). All three independent in silico predictors concur that this variant is likely benign.	revel bayesdel spliceai
BP5	Not met	BP5 requires that the variant be found in a case with an alternate molecular basis for disease. No such case data are available for NM_000455.5:c.1226G>A.
BP6	Not met	While two clinical laboratories classify NM_000455.5:c.1226G>A as likely benign and one as benign in ClinVar, these are minority opinions (3 of 16 submissions) and no expert panel or reputable source with comprehensive evidence supports a benign classification. ClinVar consensus remains VUS. BP6 is not met.	clinvar
BP7	Not met	BP7 applies to synonymous variants with no predicted splice impact. NM_000455.5:c.1226G>A is a missense variant, not a synonymous variant. BP7 does not apply.

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