Classification rationale

PM2 BP4 VUS

MYC c.872G>C

NM_002467.6:c.872G>C (p.Arg291Thr) is a missense variant in MYC, a proto-oncogene located on 8q24.21. The variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_supporting).¹ Multiple in silico predictors consistently indicate a neutral effect: REVEL 0.106, BayesDel -0.388, SpliceAI max delta 0.00 (BP4_supporting).² The variant is absent from ClinVar and has not been reported in the literature, including COSMIC; no functional, segregation, or case-control data are available.³ Overall, one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met, yielding an ACMG/AMP classification of Variant of Uncertain Significance (VUS).⁴

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 revelbayesdelspliceai ↗

3 clinvar ↗

4 generic_acmg_combination_rules

Gene diagram · NM_002467.6 · variants mapped to exon structure

MYC NM_002467.6

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1 population databases, indicating it is a rare variant.

Absent from gnomAD v2.1 (exomes/genomes).Absent from gnomAD v4.1 (exomes/genomes).

gnomad_v2 ↗gnomad_v4 ↗

✓

BP4 supporting Benign

Multiple lines of in silico evidence consistently predict a neutral or benign effect: REVEL score 0.106 (well below pathogenic threshold), BayesDel score -0.387599 (negative, favoring benign), and SpliceAI max delta score 0.00 (no predicted splicing impact).

REVEL: 0.106 (benign).BayesDel: -0.387599 (benign).SpliceAI max delta: 0.00 (no effect).

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No different pathogenic missense variant at the same amino acid position (Arg291) has been reported in ClinVar or the literature.

PS2 No de novo data are available for this variant.

PS3 No variant-specific functional data are available.

PS4 No case-control or population-based studies comparing this variant in affected versus unaffected individuals are available.

PM1 p.Arg291 does not lie within a statistically significant mutational hotspot per cancerhotspots.org.

PM5 No pathogenic variant at the same codon (Arg291) has been identified in ClinVar.

PM6 No de novo observation (without confirmation of paternity and maternity) has been reported for this variant.

PP1 No cosegregation data are available for this variant.

PP2 HCI prior scores are not available for MYC (gene not supported by the HCI prior database).

PP3 Multiple in silico predictors are benign-leaning: REVEL score 0.106 (below typical pathogenic threshold of 0.5), BayesDel score -0.387599 (negative, favoring benign), and SpliceAI max delta 0.00 (no predicted splice impact).

PP4 No patient phenotype or clinical data are available for evaluation.

PP5 This variant is absent from ClinVar; no reputable source has classified it as pathogenic.

Benign

BA1 The variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0%), far below the 1% threshold for BA1.

BS1 The variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0%), far below the 0.3% threshold for BS1.

BS2 No data available regarding observation of this variant in healthy adult individuals.

BS3 No well-established functional studies demonstrating a neutral or benign effect exist for this specific variant.

BS4 No segregation data are available to evaluate lack of cosegregation with disease.

BP1 MYC is a proto-oncogene where gain-of-function (amplification, overexpression) is the primary established disease mechanism in cancer; it is not a gene for which primarily truncating variants are known to cause disease.

BP2 No observation of this variant in trans with a known pathogenic variant has been reported.

BP5 No observation of this variant in a case with an alternative molecular basis for disease has been reported.

BP6 This variant is absent from ClinVar; no reputable source has classified it as benign.

N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.106. BayesDel score = -0.387599.

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. MYC, a transcription factor, is altered by chromosomal rearrangement, amplification and overexpression in a variety of cancer types.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

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