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.1 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.2 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 BP4.3 ClinVar reports this variant as Likely benign by two clinical laboratories and Benign by one clinical laboratory (Variation ID 719682), with criteria provided, supporting BP6.4
MYC
Final classification
Benign
BS1BS2BP4BP6
MYC
c.1085C>T
p.Ser362Phe
This variant
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS1 strong, BS2 strong, BP4 supporting, BP6 supporting; combination = 2 strong benign + 2 supporting benign, which maps to Benign.
Classification rationale
BS1BS2BP4BP6
Benign
MYC c.1085C>T
BS1 + BS2 + BP4 + BP6
→
Benign
Gene diagram
· NM_002467.6 · variants mapped to exon structure
MYC
NM_002467.6
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 13 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 · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
BS1
strong
Benign
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 v2.1 SAS: AF=0.996%305/30616 alleles3 homozygotes
✓
BS2
strong
Benign
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 v2.1: 3 homozygotes (428 heterozygotes)gnomAD v4.1: 17 homozygotes (1599 heterozygotes)
✓
BP4
supporting
Benign
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: 0.445 (below 0.5 damaging threshold)BayesDel: -0.151 (benign-leaning prediction)SpliceAI: max delta 0.00 (no predicted splicing alteration)
✓
BP6
supporting
Benign
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 Variation ID 719682: Likely benign (2 clinical labscriteria provided)Benign (1 lab
Assessed · not applied
· 13 not met · 0 not assessed
Pathogenic
PS3
No well-established in vitro or in vivo functional studies support a damaging effect on MYC.
PS4
No case-control or cohort studies demonstrate enrichment of this variant in affected individuals.
PM1
This variant does not lie in a statistically significant mutational hotspot or well-established critical functional domain.
PM2
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%).
PP1
No segregation data are available for this variant.
PP2
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.
PP3
Multiple in silico predictors do not support a deleterious effect.
PP4
No patient phenotype or clinical data specific to this variant are available.
PP5
ClinVar reports this variant as Likely benign (2 clinical laboratories) and Benign (1 clinical laboratory).
Benign
BA1
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%.
BS3
No well-established in vitro or in vivo functional studies demonstrate no damaging effect on MYC protein function for p.Ser362Phe.
BS4
No segregation data demonstrating lack of cosegregation with disease are available for this variant.
BP1
MYC is primarily known as a somatic oncogene, not a gene where primarily truncating variants cause a specific Mendelian germline disorder.
N/A · 8
PVS1 · PS1 · PS2 · PM5 · PM6 · BP2 · BP5 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000990658; MAF= 0.09907%, 1599/1614078 alleles, homozygotes = 17) and has highest observed frequency in the South Asian population (AF= 0.0103215; MAF= 1.03215%, 940/91072 alleles, homozygotes = 14); grpmax FAF= 0.00977366.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00151455; MAF= 0.15146%, 428/282592 alleles, homozygotes = 3) and has highest observed frequency in the South Asian population (AF= 0.00996211; MAF= 0.99621%, 305/30616 alleles, homozygotes = 3); grpmax FAF= 0.00904243.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0013572204125950054, 25/18420 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.099%
· 1599 / 1,614,078
17 hom · FAF 0.98%
17 hom · FAF 0.98%
South Asian 940 / 91,072 |
1% 14 hom |
Middle Eastern 52 / 6,062 |
0.86% 2 hom |
Remaining individuals 78 / 62,510 |
0.12% |
Admixed American 40 / 60,014 |
0.067% |
European (non-Finnish) 485 / 1,180,024 |
0.041% 1 hom |
African/African American 4 / 74,994 |
0.0053% |
+ 4 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish)
gnomAD v2.1
0.15%
· 428 / 282,592
3 hom · FAF 0.9%
3 hom · FAF 0.9%
South Asian 305 / 30,616 |
1% 3 hom |
Remaining individuals 15 / 7,222 |
0.21% |
Admixed American 25 / 35,432 |
0.071% |
European (non-Finnish) 83 / 128,956 |
0.064% |
+ 4 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish))
gnomAD Canada 🇨🇦
0.14%
· 25 / 18,420
0 hom · FAF 0.45%
0 hom · FAF 0.45%
South Asian 11 / 1,362 |
0.81% |
Remaining individuals 4 / 1,138 |
0.35% |
East Asian 3 / 1,338 |
0.22% |
Latino/Admixed American 1 / 838 |
0.12% |
European (non-Finnish) 6 / 11,740 |
0.051% |
+ 4 not observed (African/African American, Ashkenazi Jewish, European (Finnish), Middle Eastern)
ClinVar
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 719682)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.445. BayesDel score = -0.151424.
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.
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; COSV99420567, n = 4 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 2 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
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR