Classification rationale

VUS

RNF43 c.662G>A missense · exon 6

No pathogenic or benign criterion was met or applied; under the generic ACMG/AMP 2015 combination rules, that leaves the variant classified as Variant of Uncertain Significance.

Gene diagram · NM_017763.6 · variants mapped to exon structure

RNF43 NM_017763.6

Fetching transcript structure from UCSC…

Applied criteria · 0 applied · 24 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 0

No criteria were applied for this variant.

Assessed · not applied · 2 not met · 22 not assessed

Pathogenic

PS1 Not assessed: insufficient evidence was available to determine whether the identical amino acid change is an established pathogenic substitution.

PS2 Not assessed: no proband or parental genotype data existed, so a confirmed de novo occurrence could not be evaluated.

PS3 Not assessed: no functional study of p.(Arg221Gln) was available to demonstrate a damaging effect on protein function.

PS4 Not assessed: no case-control study of this variant exists, and its gnomAD frequency (0.49% overall, 6.0% East Asian) resembles a common polymorphism rather than a rare disease allele.

PM1 Not assessed: insufficient evidence was available to determine whether p.(Arg221Gln) falls in a mutational hotspot or critical protein domain.

PM2 Not assessed: insufficient evidence was available to evaluate the variant's rarity in population databases.

PM3 Not assessed: no observation of this variant in trans with a pathogenic allele exists, and germline RNF43 disease is primarily autosomal dominant.

PM5 Not assessed: insufficient evidence was available to identify another pathogenic substitution at the same amino acid position.

PM6 Not assessed: no proband or parental genotype data existed, so an assumed de novo occurrence could not be evaluated.

PP1 Not assessed: no affected relatives were tested, so co-segregation of this variant with disease could not be evaluated.

PP2 Not assessed: insufficient evidence was available to evaluate whether missense is a common disease mechanism in RNF43.

PP3 Not assessed: insufficient evidence was available from in silico predictions to evaluate this criterion.

PP4 Not assessed: no proband phenotype or family history was available, so phenotype specificity could not be evaluated.

PP5 Not met: no ClinVar expert panel has classified this exact variant as Pathogenic or Likely pathogenic; all eight submissions are from clinical laboratories.

Benign

BA1 Not assessed: insufficient evidence was available to evaluate the variant against the BA1 population-frequency threshold.

BS1 Not assessed: insufficient evidence was available to evaluate the variant against the BS1 population-frequency threshold.

BS2 Not assessed: insufficient evidence was available to evaluate the variant's occurrence in healthy individuals.

BS3 Not assessed: no functional study of p.(Arg221Gln) was available to demonstrate a lack of damaging effect.

BS4 Not assessed: no affected relatives were tested, so the variant could neither be shown to segregate nor fail to segregate.

BP1 Not assessed: insufficient evidence was available to evaluate whether loss-of-function is the predominant disease mechanism for RNF43.

BP2 Not assessed: no cis or trans co-occurrence with a pathogenic RNF43 variant was observed, and the dominant disorder is not fully penetrant.

BP4 Not assessed: insufficient evidence was available from in silico predictions to evaluate this criterion.

BP5 Not assessed: no proband-level data existed to evaluate whether an alternative genetic cause explains the presentation.

BP6 Not met: no ClinVar expert panel has classified this exact variant as Benign or Likely benign; the eight laboratory submissions do not qualify.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.00245905; MAF= 0.24590%, 3956/1608752 alleles, homozygotes = 143) and has highest observed frequency in the East Asian population (AF= 0.0719542; MAF= 7.19542%, 3207/44570 alleles, homozygotes = 136); grpmax FAF= 0.0698771.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00487775; MAF= 0.48777%, 1351/276972 alleles, homozygotes = 31) and has highest observed frequency in the East Asian population (AF= 0.0602779; MAF= 6.02779%, 1180/19576 alleles, homozygotes = 30); grpmax FAF= 0.0577767.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.00499457111834962, 92/18420 alleles, homozygotes = 3).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.25% · 3956 / 1,608,752
143 hom · FAF 7%

East Asian 3207 / 44,570	7.2% 136 hom
Middle Eastern 45 / 6,048	0.74% 2 hom
South Asian 304 / 90,474	0.34% 2 hom
Remaining individuals 203 / 62,294	0.33% 3 hom
Admixed American 23 / 59,626	0.039%
African/African American 25 / 74,868	0.033%
European (non-Finnish) 148 / 1,177,288	0.013%
European (Finnish) 1 / 63,318	0.0016%

+ 2 not observed (Amish, Ashkenazi Jewish)

gnomAD v2.1

0.49% · 1351 / 276,972
31 hom · FAF 5.8%

East Asian 1180 / 19,576	6% 30 hom
South Asian 110 / 30,030	0.37% 1 hom
Remaining individuals 15 / 7,026	0.21%
African/African American 14 / 24,746	0.057%
Admixed American 11 / 34,648	0.032%
European (non-Finnish) 21 / 126,516	0.017%

+ 2 not observed (Ashkenazi Jewish, European (Finnish))

gnomAD Canada 🇨🇦

0.5% · 92 / 18,420
3 hom · FAF 4.8%

East Asian 78 / 1,338	5.8% 3 hom
Remaining individuals 5 / 1,138	0.44%
South Asian 2 / 1,362	0.15%
European (non-Finnish) 7 / 11,740	0.06%

+ 5 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, European (Finnish), Middle Eastern)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (8 clinical laboratories). (ClinVarID = 1169480)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.092. BayesDel score = -0.435542.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RNF43, a ubiquitin ligase, is mutated in various cancers including gastrointestinal and gynecological cancers.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV68457520, n = 3 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 4 PMIDs not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version. CLINVAR

26389505 ↗ Genetics of Colorectal Cancer (PDQ®): Health Professional Version. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR