Variant classification summary

NM_002467.6:c.1085C>T

MYC · NP_002458.2:p.(Ser362Phe) · NM_002467.6

GRCh37: chr8:128752924 C>T · GRCh38: chr8:127740678 C>T

Gene: MYC Transcript: NM_002467.6

Final call

Benign

BS1 strong BS2 strong BP4 supporting BP6 supporting

Variant details

Gene

MYC

Transcript

NM_002467.6

Protein

NP_002458.2:p.(Ser362Phe)

gnomAD AF

0.0009906584440157167 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002467.6:c.1085C>T (p.Ser362Phe) is present at a grpmax filtering allele frequency of 0.977% in the South Asian population of gnomAD v4.1, exceeding the BS1 threshold of >0.3%, which indicates the variant is too common to be a fully penetrant pathogenic allele for a rare Mendelian disorder.

2

This variant has been observed in 17 homozygous individuals in gnomAD v4.1, which is incompatible with a fully penetrant early-onset dominant disorder, meeting BS2 at strong benign strength.

3

Multiple computational predictors indicate a benign effect: REVEL score 0.445 (below 0.5 threshold), BayesDel −0.151 (benign-leaning), and SpliceAI max delta 0.00 (no predicted splicing impact), supporting BP4.

4

ClinVar reports this variant as Likely benign by two clinical laboratories and Benign by one clinical laboratory (Variation ID 719682), with criteria provided, supporting BP6.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

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_002467.6:c.1085C>T is a missense variant (p.Ser362Phe), not a null variant (nonsense, frameshift, or canonical splice ±1,2). The generic PVS1 framework per PMC6185798 does not apply.	pvs1_variant_assessment
PS1	N/A	No known pathogenic missense variant at residue Ser362 has been established. No comparator pathogenic variant with the same amino acid change from a different nucleotide change was identified.	pm5_candidates
PS2	N/A	No de novo data available for this variant; no trio or parentage studies were identified.
PS3	Not met	No well-established in vitro or in vivo functional studies support a damaging effect on MYC. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific functional evidence. No publications with functional data for p.Ser362Phe were identified.	oncokb
PS4	Not met	No case-control or cohort studies demonstrate enrichment of this variant in affected individuals. ClinVar contains only benign/likely benign classifications.	clinvar
PS5	N/A	No de novo reports exist for this variant; PS5 requires a de novo observation with confirmed maternity/paternity but without full parental confirmation.
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot or well-established critical functional domain. The hotspot analysis found residue_significant=false.
PM2	Not met	This variant is present in gnomAD population databases at frequencies above the PM2 threshold of <0.1% (v2.1 overall AF=0.151%; v4.1 overall AF=0.099%). The presence of 17 homozygous individuals in v4.1 further argues against rarity. PM2 is not met.	gnomad_v2 gnomad_v4
PM5	N/A	No pathogenic missense variant at the same residue (Ser362) with a different amino acid change was identified in ClinVar. The pm5 candidate search returned no same-residue comparator variants.	pm5_candidates
PM6	N/A	No de novo observations have been reported for this variant.
PP1	Not met	No segregation data are available for this variant. No family studies with cosegregation analysis were identified.
PP2	Not met	MYC is not an established gene with a low rate of benign missense variation for which missense variants are a common mechanism of germline disease. MYC is primarily known as a somatic oncogene; its germline disease association is tenuous.	pvs1_gene_context
PP3	Not met	Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.445 (below the 0.5 damaging threshold), BayesDel is −0.151 (benign-leaning), and SpliceAI predicts no splicing impact (max delta 0.00).	revel bayesdel spliceai
PP4	Not met	No patient phenotype or clinical data specific to this variant are available. No case reports describing individuals harboring this variant with a consistent phenotype were identified.
PP5	Not met	ClinVar reports this variant as Likely benign (2 clinical laboratories) and Benign (1 clinical laboratory). No reputable source reports it as pathogenic.	clinvar
BA1	Not met	The highest population frequency (grpmax FAF) is 0.977% in gnomAD v4.1 (South Asian), which is below the non-VCEP BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Met	The allele frequency in the South Asian population (grpmax FAF 0.977% in gnomAD v4.1, 0.904% in v2.1) exceeds the non-VCEP BS1 threshold of >0.3%, indicating the variant is too common to be a fully penetrant pathogenic allele for a rare Mendelian disorder.	gnomad_v2 gnomad_v4
BS2	Met	This variant has been observed in 17 homozygous individuals in gnomAD v4.1 and 3 homozygous individuals in v2.1. Homozygosity at this frequency is incompatible with a fully penetrant early-onset dominant Mendelian disorder.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate no damaging effect on MYC protein function for p.Ser362Phe. No variant-specific functional studies were identified.	oncokb
BS4	Not met	No segregation data demonstrating lack of cosegregation with disease are available for this variant.
BP1	Not met	MYC is primarily known as a somatic oncogene, not a gene where primarily truncating variants cause a specific Mendelian germline disorder. The germline disease context is limited and does not establish missense variants as secondary to a predominantly truncating mechanism.	pvs1_gene_context
BP2	N/A	No data on trans or cis configurations with known pathogenic variants are available.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.445 (below the 0.5 damaging threshold), BayesDel is −0.151 (benign-leaning), and SpliceAI predicts no splicing impact (max delta 0.00).	revel bayesdel spliceai
BP5	N/A	No case data identifying an alternate molecular basis for disease in a proband carrying this variant are available.
BP6	Met	ClinVar reports this variant as Likely benign by 2 clinical laboratories (Labcorp Genetics/Invitae and King Faisal Specialist Hospital) and Benign by 1 laboratory (Breakthrough Genomics), all with criteria provided. The aggregate classification is Likely benign (Variation ID 719682).	clinvar
BP7	N/A	NM_002467.6:c.1085C>T is a missense variant (p.Ser362Phe), not a synonymous variant. BP7 applies only to silent/synonymous variants.

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