NM_001126049.2:c.373C>T

KLLN · NP_001119521.1:p.(Arg125Trp) · NM_001126049.2

GRCh37: chr10:89621872 G>A · GRCh38: chr10:87862115 G>A

Gene: KLLN Transcript: NM_001126049.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

KLLN

Transcript

NM_001126049.2

Protein

NP_001119521.1:p.(Arg125Trp)

gnomAD AF

4.4648172401476365e-05 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001126049.2:c.373C>T (p.Arg125Trp) is a missense variant in KLLN, a gene implicated in Cowden syndrome and Cowden-like syndrome through germline promoter hypermethylation.

This variant is absent from ClinVar and has not been reported as pathogenic or benign by any clinical laboratory or expert panel.

In gnomAD v4.1, the variant is observed at an extremely low allele frequency (0.00446%, 69/1,545,416 alleles, 0 homozygotes; grpmax FAF=4.68e-05), meeting PM2 at supporting strength. The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0.

Multiple in silico predictors do not support a deleterious effect: REVEL score is 0.138 (low, below typical pathogenic thresholds), BayesDel score is -0.085 (benign direction), and SpliceAI predicts no splice impact (max delta 0.00). These concordant benign predictions meet BP4 at supporting strength.

No variant-specific functional studies, case-control data, de novo observations, family segregation data, or clinical phenotype information are available. PVS1 is not applicable to this missense variant; PM1, PS3, PS4, PM5, PM6, PP1, PP2, PP4, PP5, BA1, BS1, BS2, BS3, BS4, BP1, BP2, BP5, and BP6 are not met due to insufficient evidence.

Applying the generic ACMG/AMP 2015 combination rules (PMID:25741868): one supporting pathogenic criterion (PM2_Supporting) and one supporting benign criterion (BP4_Supporting) are present. These offset, resulting in a final classification of Variant of Uncertain Significance (VUS).

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	This is a missense variant (c.373C>T, p.Arg125Trp). It 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 to missense variants under the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework
PS1	Not met	No pathogenic or likely pathogenic variant at the same amino acid position (Arg125) has been established in ClinVar or the literature to support that this same amino acid change is known to be pathogenic.	clinvar
PS2	Not met	No de novo data with confirmed maternity and paternity are available for this variant.
PS3	Not met	No well-established in vitro or in vivo functional studies have been identified for this specific variant. The available KLLN literature addresses promoter methylation and gene-level function but does not report functional data for NM_001126049.2:c.373C>T.
PS4	Not met	No case-control or cohort data demonstrate a statistically significant enrichment of this variant in affected individuals versus controls.
PS5	Not met	This variant is absent from ClinVar. No reputable sources have reported it as pathogenic.	clinvar
PM1	Not met	This variant does not lie within a statistically significant mutational hotspot in COSMIC or Cancer Hotspots, and no well-established critical functional domain has been defined for KLLN where missense variants are enriched in disease.
PM2	Met	This variant is present in gnomAD v4.1 at an extremely low allele frequency (AF=0.00446%, 69/1,545,416 alleles, 0 homozygotes; grpmax FAF=4.68e-05), well below the 0.1% threshold. The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0.	gnomad_v4 gnomad_v2 gnomad_canada
PM5	Not met	No pathogenic or likely pathogenic missense variants at the same amino acid residue (Arg125) with a different alternate amino acid have been identified in ClinVar or the literature. No comparator candidates were found for PM5 assessment.	clinvar pm5_candidates
PM6	Not met	No de novo observation (with or without confirmed parentage) has been reported for this variant.
PP1	Not met	No cosegregation data in affected family members are available for this variant.
PP2	Not met	No gene-level missense constraint metrics (e.g., missense Z-score, HCI prior probability) are available for KLLN to assess whether the gene has a low rate of benign missense variation.
PP3	Not met	Multiple in silico predictors do not support a damaging effect. REVEL score is 0.138 (below typical pathogenic thresholds), BayesDel score is -0.085 (benign direction), and SpliceAI predicts no splice impact (max delta = 0.00). These results are not consistent with a deleterious prediction.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data are available for this variant. No information about the clinical presentation of individuals carrying this variant has been provided.
PP5	Not met	No reputable source (clinical laboratory, expert panel, or research group) has reported this variant as pathogenic in ClinVar or the literature.	clinvar
BA1	Not met	The allele frequency in gnomAD v4.1 is 0.00446% (69/1,545,416), which is well below the 1% threshold for BA1.	gnomad_v4
BS1	Not met	The allele frequency in gnomAD v4.1 is 0.00446% (69/1,545,416), which is well below the 0.3% threshold for BS1.	gnomad_v4
BS2	Not met	Although 69 alleles are observed in gnomAD v4.1 (a general population database), BS2 requires observation in a healthy adult for a disorder with full penetrance expected at an early age. Cowden syndrome/PTEN hamartoma tumor syndrome exhibits age-related penetrance, and no specific adult control genotype-phenotype data are available for this variant to satisfy BS2.	gnomad_v4
BS3	Not met	No well-established functional studies demonstrating no damaging effect have been identified for NM_001126049.2:c.373C>T.
BS4	Not met	No nonsegregation data in affected families are available for this variant.
BP1	Not met	BP1 applies when a missense variant occurs in a gene for which primarily truncating variants cause disease. While KLLN loss of function is implicated in Cowden syndrome, the established germline disease mechanism is promoter hypermethylation (epigenetic silencing) rather than coding truncating variants. The variant spectrum of KLLN in germline disease is not sufficiently defined to apply BP1.
BP2	Not met	No observation of this variant in trans with a known pathogenic variant in KLLN or PTEN has been reported for a fully penetrant dominant disorder.
BP4	Met	Multiple lines of computational evidence suggest no deleterious impact. The REVEL score is 0.138 (below the 0.5 threshold commonly associated with pathogenicity), the BayesDel score is -0.085 (in the benign range; negative values favor benign), and SpliceAI predicts no splice alteration (max delta = 0.00). These concordant predictions from independent in silico tools support a benign interpretation.	revel bayesdel spliceai
BP5	Not met	No observation of this variant in a case with an alternative established molecular basis for disease has been reported.
BP6	Not met	No reputable source has reported this variant as benign in ClinVar or the literature.	clinvar
BP7	N/A	This is a missense variant (c.373C>T, p.Arg125Trp), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact.	spliceai
BP3	N/A	This is a substitution variant, not an in-frame indel. BP3 applies only to in-frame deletions or insertions in non-repeat regions.
PM3	N/A	KLLN-associated Cowden syndrome is an autosomal dominant disorder. PM3 applies only to recessive disorders where a variant is observed in trans with a pathogenic variant.
PM4	N/A	This is a single nucleotide substitution producing a missense change, not a protein-length-altering variant (in-frame indel, stop-loss, or initiation codon change). PM4 is not applicable.

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