Variant classification summary

NM_017763.5:c.1196C>T

RNF43 · NP_060233.3:p.(Pro399Leu) · NM_017763.5

GRCh37: chr17:56435941 G>A · GRCh38: chr17:58358580 G>A

Gene: RNF43 Transcript: NM_017763.5

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

RNF43

Transcript

NM_017763.5

Protein

NP_060233.3:p.(Pro399Leu)

gnomAD AF

0.0 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_017763.5:c.1196C>T (p.Pro399Leu) is absent from gnomAD v2.1 (0/223,892 alleles) and v4.1 (0/1,595,338 alleles), meeting PM2 at supporting strength.

2

Multiple in silico tools predict a benign effect: REVEL score 0.022, BayesDel score -0.736863, and SpliceAI max delta 0.01 with no predicted splice impact, meeting BP4 at supporting benign strength.

3

The variant is reported in ClinVar as Uncertain Significance by a single clinical testing laboratory (VariationID 2093022) with review status 'criteria provided, single submitter.' This does not satisfy PP5 or BP6 thresholds.

4

The variant is a missense substitution outside known null-variant buckets, so PVS1 is not applicable. No functional studies, segregation data, de novo observations, case-control evidence, or same-residue pathogenic comparators are available for this variant.

5

Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are present. These are at equal weight and do not meet any pathogenic, likely pathogenic, benign, or likely benign combination threshold.

6

Final classification: 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_017763.5:c.1196C>T is a missense variant (p.Pro399Leu) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for generic PVS1 activation per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No pathogenic missense variant at the same amino acid residue (Pro399) with an established pathogenic mechanism has been identified; PM5 candidate harvesting confirmed no same-residue comparator is available.	pm5_candidates
PS2	Not met	No de novo observation of NM_017763.5:c.1196C>T has been reported in the available literature or ClinVar submissions.
PS3	Not assessed	No variant-specific functional studies for NM_017763.5:c.1196C>T (p.Pro399Leu) were identified in the literature or OncoKB. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no curated functional evidence.	oncokb
PS4	Not met	No case-control or statistical evidence demonstrates enrichment of NM_017763.5:c.1196C>T in affected individuals compared to controls.
PS5	N/A	Requires two independent de novo observations with confirmed maternity/paternity; no de novo reports exist for this variant.
PM1	Not met	The variant does not lie in a statistically significant mutational hotspot as determined by cancerhotspots.org, and no known functional domain with established pathogenic missense constraint has been demonstrated to include residue Pro399.
PM2	Met	NM_017763.5:c.1196C>T is absent from population databases: gnomAD v2.1 (0/223,892 alleles), gnomAD v4.1 (0/1,595,338 alleles), and gnomAD-Canada v1.0. The observed allele frequency of 0.0% is well below the 0.1% PM2 threshold for rare variants.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic missense variant at the same amino acid residue (Pro399) with a different amino acid change was identified; PM5 candidate search returned zero same-residue comparators.	pm5_candidates
PM6	N/A	Requires a de novo observation without confirmed maternity/paternity; no de novo reports exist for this variant.
PP1	Not met	No segregation data are available for NM_017763.5:c.1196C>T; no co-segregation with disease in affected family members has been reported.
PP2	Not met	RNF43 is not established as a gene where missense variants are the predominant pathogenic mechanism with a low rate of benign missense variation. Pathogenic RNF43 variants include both truncating and missense alterations across multiple disease contexts.
PP3	Not met	Multiple in silico tools predict a benign effect: REVEL score 0.022 (strongly benign-leaning, well below typical pathogenic threshold of ~0.5), BayesDel score -0.736863 (benign-leaning), and SpliceAI max delta 0.01 (no predicted splice impact). No computational evidence supports pathogenicity.	revel bayesdel spliceai
PP4	Not met	No phenotype specificity data are available; the variant has not been reported in a cohort where its presence is highly specific to a defined clinical presentation.
PP5	Not met	ClinVar reports this variant as Uncertain Significance (VariationID 2093022) from a single clinical testing laboratory (Labcorp Genetics/Invitae) with review status 'criteria provided, single submitter.' This does not constitute a reputable source reporting the variant as pathogenic.	clinvar
BA1	Not met	NM_017763.5:c.1196C>T is absent from gnomAD (AF=0.0% in both v2.1 and v4.1), far below the 1% BA1 threshold for a benign stand-alone classification.	gnomad_v2 gnomad_v4
BS1	Not met	NM_017763.5:c.1196C>T is absent from gnomAD (AF=0.0% in both v2.1 and v4.1), far below the 0.3% BS1 threshold for a strong benign criterion.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available regarding observation of this variant in homozygous state or in healthy adult controls. The variant is absent from gnomAD and no family studies are available.
BS3	Not assessed	No variant-specific functional studies demonstrating no deleterious effect for NM_017763.5:c.1196C>T (p.Pro399Leu) have been identified. OncoKB reports no curated functional evidence for this alteration.	oncokb
BS4	Not met	No segregation data in unaffected family members are available for this variant.
BP1	Not met	RNF43 is not a gene where only truncating variants cause disease. Reported pathogenic variants in RNF43 include both missense and truncating alterations across serrated polyposis syndrome and other phenotypes. This missense variant does not qualify for BP1.	pvs1_gene_context
BP2	Not met	No evidence that NM_017763.5:c.1196C>T has been observed in trans with a known pathogenic variant in RNF43.
BP4	Met	Multiple in silico tools consistently predict a benign effect: REVEL score 0.022 (strongly benign-leaning, well below pathogenic threshold), BayesDel score -0.736863 (benign-leaning), and SpliceAI max delta 0.01 (no predicted splicing impact). The convergent benign prediction from independent algorithms supports BP4 at supporting benign strength.	revel bayesdel spliceai
BP5	Not met	No alternative molecular basis for disease has been identified in a case where this variant was observed.
BP6	Not met	ClinVar reports NM_017763.5:c.1196C>T as Uncertain Significance (VariationID 2093022) from a single submitter. The classification is not benign or likely benign from a reputable source, which is required for BP6.	clinvar
BP7	N/A	BP7 applies only to synonymous (silent) variants with no predicted splice impact. NM_017763.5:c.1196C>T is a missense variant (p.Pro399Leu), not synonymous.

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