NM_001033082.2:c.961C>G

MYCL · NP_001028254.2:p.(Arg321Gly) · NM_001033082.2

GRCh37: chr1:40363268 G>C · GRCh38: chr1:39897596 G>C

Gene: MYCL Transcript: NM_001033082.2

Final call

VUS

PM2 moderate PP3 supporting

Variant details

Gene

MYCL

Transcript

NM_001033082.2

Protein

NP_001028254.2:p.(Arg321Gly)

gnomAD AF

2.4780107520886533e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Moderate): variant is at extremely low population frequency — gnomAD v2.1 AF 3.98e-06 and v4.1 AF 2.48e-06, well below the <0.1% threshold, zero homozygotes.

PP3 (Supporting): REVEL 0.914 and BayesDel 0.499 both predict a deleterious missense effect.

One moderate plus one supporting criterion meets no generic ACMG/AMP 2015 combination rule, yielding Variant of Uncertain Significance (VUS).

Final determination: Under the generic ACMG/AMP 2015 combination rules, the applied criteria (PM2 moderate + PP3 supporting = 1 moderate + 1 supporting) satisfy no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination, so the variant is classified as Variant of Uncertain Significance (VUS).

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	Not applicable: this is a missense substitution, so no null-variant mechanism — nonsense-mediated decay, truncation, or splice disruption — is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no alternate-nucleotide variant producing p.Arg321Gly is established as pathogenic; the only ClinVar record is this variant itself (VUS).	clinvar pm5_candidates generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband, parental-testing, or trio data were available to evaluate a de novo occurrence.	generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no wet-lab functional study of this variant was available in either direction.	oncokb clinvar spliceai revel bayesdel generic_acmg_combination_rules
PS4	Not assessed	Not assessed: no case-control or cohort study of this variant exists to demonstrate enrichment in affected individuals.	clinvar gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM1	Not met	Not met: no mutational hotspot or critical functional domain is documented at MYCL Arg321, and no benign-variation constraint was established.	oncokb generic_acmg_combination_rules
PM2	Met	Met (moderate): gnomAD v2.1 AF 3.98e-06 and v4.1 AF 2.48e-06, both far below the <0.1% threshold, with zero homozygotes.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no allele-phase or segregation data exist, and MYCL has no established autosomal-recessive germline disease association.
PM4	N/A	Not applicable: missense substitution causes no protein-length change, so there is nothing for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no alternate missense change at Arg321 is established as pathogenic; flagged for human review.	pm5_candidates clinvar generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no proband observation or parental-testing status is available to evaluate an assumed de novo occurrence.	generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no pedigree, affected relatives, or segregation data exist for this variant.	generic_acmg_combination_rules
PP2	Not met	Not met: missense is not MYCL's disease mechanism — it is activated by amplification — and no missense constraint data support a low benign-missense rate.	oncokb generic_acmg_combination_rules
PP3	Met	Met (supporting): REVEL 0.914 and BayesDel 0.499 both predict a deleterious missense effect.	revel bayesdel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family history data were available.	clinvar generic_acmg_combination_rules
PP5	Not met	Not met: no ClinVar expert-panel pathogenic classification exists for this exact variant — only a single-submitter laboratory VUS.	clinvar
BA1	Not met	Not met: gnomAD v2.1 AF 3.98e-06 and v4.1 AF 2.48e-06 are orders of magnitude below the >1% BA1 threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: observed allele frequencies (max 0.00088%) are far below the >0.3% threshold, and no disease-allele expectation applies.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2	N/A	Not applicable: MYCL has no established monogenic germline disorder, so penetrance in healthy adults cannot be evaluated.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no functional study demonstrating normal function was available.	oncokb clinvar spliceai revel bayesdel generic_acmg_combination_rules
BS4	Not assessed	Not assessed: no family data exist to evaluate non-segregation in affected relatives.	generic_acmg_combination_rules
BP1	Not met	Not met: MYCL is an oncogene activated by amplification, not a gene whose disease mechanism is truncation.	oncokb generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no pathogenic second variant or allele-phase data exist to evaluate cis/trans configuration.
BP3	N/A	Not applicable: missense substitution does not alter protein length within a repeat region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.914 and BayesDel 0.499 both predict a deleterious effect, directly contradicting a no-impact conclusion.	spliceai revel bayesdel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband-level data on an alternate molecular basis for disease were available.	clinvar generic_acmg_combination_rules
BP6	Not met	Not met: no ClinVar expert-panel benign or likely-benign classification exists for this exact variant.	clinvar
BP7	N/A	Not applicable: this is a missense substitution, not a synonymous variant.	generic_acmg_combination_rules

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