NM_000075.4:c.823A>T (p.Met275Leu) is a missense variant in CDK4, a gene in which missense variants are a known mechanism of autosomal dominant hereditary melanoma.1 This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=3.98e-6 (1/251,446 alleles) and gnomAD v4.1 AF=1.86e-6 (3/1,612,194 alleles; grpmax FAF=6.8e-7), satisfying PM2 at supporting level.2 The variant meets PP2 at supporting level: CDK4 has a low rate of benign missense variation and missense variants are a well-established disease mechanism (e.g., R24C/H in hereditary melanoma).3 Multiple lines of in silico evidence support a benign interpretation: REVEL score 0.197 (<0.5), BayesDel score -0.0628 (negative), and SpliceAI max delta 0.00 (no splicing impact), satisfying BP4 at supporting benign level.4 This variant has been reported in ClinVar as Uncertain Significance by three clinical laboratories (Variation ID 141405). No functional studies, segregation data, case-control comparisons, or de novo observations are available for this variant.5 Two supporting pathogenic criteria (PM2, PP2) and one supporting benign criterion (BP4) net to one supporting pathogenic criterion, resulting in a final classification of Variant of Uncertain Significance (VUS) under the generic ACMG/AMP 2015 framework.6
CDK4
Final classification
VUS
CDK4 c.823A>T · p.Met275Leu
CDK4
NM_000075.4:c.823A>T (p.Met275Leu) is a missense variant in CDK4, a gene in which missense variants are a known mechanism of autosomal dominant hereditary melanoma.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP2 supporting, BP4 supporting benign; combination = 2 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2PP2
BP4
VUS
CDK4 c.823A>T
PM2 + PP2 + BP4
→
VUS
4
revelbayesdelspliceai ↗
6
generic_acmg_combination_rules
Gene diagram
· NM_000075.4 · variants mapped to exon structure
CDK4
NM_000075.4
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
Population frequency
Overall AF
3 / 1,612,194
0.00019%
Highest · European (non-Finnish)
0.00025%
Homozygotes
0
grpmax FAF
6.8e-05%
Allele frequency by ancestry — gnomAD v4.1
observed in 1 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (non-Finnish) | 3 / 1,178,216 | 0.00025% | 0 |
| Admixed American | 0 / 60,026 | — | — |
| European (Finnish) | 0 / 64,018 | — | — |
| Amish | 0 / 912 | — | — |
| East Asian | 0 / 44,882 | — | — |
| Middle Eastern | 0 / 6,060 | — | — |
| South Asian | 0 / 91,056 | — | — |
| Ashkenazi Jewish | 0 / 29,590 | — | — |
| African/African American | 0 / 75,004 | — | — |
“
This variant is present in gnomAD v4.1 (AF= 1.86082e-06; MAF= 0.00019%, 3/1612194 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54622e-06; MAF= 0.00025%, 3/1178216 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
Overall AF
1 / 251,446
0.0004%
Highest · European (non-Finnish)
0.00088%
Homozygotes
0
Allele frequency by ancestry — gnomAD v2.1
observed in 1 of 8 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (non-Finnish) | 1 / 113,740 | 0.00088% | 0 |
| African/African American | 0 / 16,248 | — | — |
| Admixed American | 0 / 34,588 | — | — |
| Ashkenazi Jewish | 0 / 10,076 | — | — |
| East Asian | 0 / 18,394 | — | — |
| European (Finnish) | 0 / 21,648 | — | — |
| Remaining individuals | 0 / 6,138 | — | — |
| South Asian | 0 / 30,614 | — | — |
“
This variant is present in gnomAD v2.1 (AF= 3.977e-06; MAF= 0.00040%, 1/251446 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79198e-06; MAF= 0.00088%, 1/113740 alleles, homozygotes = 0).
“
This variant is absent from gnomAD-Canada.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 141405)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.197. BayesDel score = -0.0628374.
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. CDK4, an intracellular kinase, is altered by amplification or mutation in various cancer types including soft tissue sarcomas and gliomas.
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.
Literature · 4 PMIDs triaged · 3 high-priority
4papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
25394175 ↗
case observation
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
The practice guidelines of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) are developed by members of the ACMG and NSGC to assist medical geneticists, genetic counselors, and other health-care providers in making decisions about appropriate management of genetic concerns, including access to and/or delivery of services. Each pract
PP5PS4
28492532 ↗
background review
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
PP5PS4
Sources & reference links