PM2 (supporting) is met: the variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=6.20e-7, 1/1,613,138 alleles), well below the 0.1% threshold.1 BP4 (supporting benign) is met: multiple lines of computational evidence (REVEL 0.104, BayesDel -0.262, SpliceAI max delta 0.01) consistently predict no impact on gene product.2 The total evidence weight is one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4). Under generic ACMG/AMP 2015 combination rules, this does not meet the threshold for Likely Pathogenic (requires ≥2 supporting), Likely Benign (requires ≥2 supporting benign), or any other classification tier. The variant is classified as a Variant of Uncertain Significance (VUS).3
CDK12
Final classification
VUS
CDK12 c.1601C>T · p.Ser534Phe
CDK12
PM2 (supporting) is met: the variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=6.20e-7, 1/1,613,138 alleles), well below the 0.1% threshold.
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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
CDK12 c.1601C>T
PM2 + BP4
→
VUS
Gene diagram
· NM_016507.4 · variants mapped to exon structure
CDK12
NM_016507.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
The variant is absent from gnomAD v2.1 and present at an extremely low allele frequency in gnomAD v4.1 (AF=6.20e-7; 1/1,613,138 alleles; 0 homozygotes), well below the 0.1% threshold for PM2.
gnomAD v2.1: absent.gnomAD v4.1: 1 allele out of 1613
✓
BP4
supporting
Benign
Multiple lines of computational evidence consistently predict no impact on gene product: REVEL score 0.104 (benign range), BayesDel score -0.262 (benign range), and SpliceAI max delta 0.01 (no predicted splice effect). Three independent in silico tools uniformly suggest a benign effect.
REVEL: 0.104 (benignbelow 0.29 threshold).BayesDel: -0.262 (benign range).
Assessed · not applied
Pathogenic
PS1
No evidence that the same amino acid change (p.Ser534Phe) has been previously established as pathogenic in ClinVar, literature, or other curated databases.
PS2
No de novo observation with confirmed maternity and paternity has been reported for this variant.
PS3
No well-established functional studies demonstrating a damaging effect have been identified for this variant.
PS4
No case-control or cohort prevalence data comparing the frequency of this variant in affected individuals versus controls is available.
PM1
The variant (p.Ser534Phe) is not located in a statistically significant mutational hotspot per CancerHotspots.org.
PM5
No same-residue pathogenic comparator variant was identified.
PM6
No assumed de novo observation (without confirmation of paternity and maternity) has been reported for this variant.
PP1
No cosegregation data with disease in multiple affected family members is available for this variant.
PP2
No HCI prior score is available for CDK12.
PP3
Multiple lines of in silico evidence predict a benign effect: REVEL score 0.104 (benign range, below 0.29 threshold) and BayesDel score -0.262 (benign range).
PP4
No patient phenotype or family history data are available for this case to assess specificity for CDK12-associated disease.
PP5
ClinVar classification is Uncertain Significance (1-star, criteria provided, single submitter, Ambry Genetics).
Benign
BA1
The variant allele frequency in gnomAD v4.1 is 6.20e-7 (0.000062%), far below the 1% threshold required for BA1.
BS1
The variant allele frequency in gnomAD v4.1 is 6.20e-7, far below the 0.3% threshold for BS1.
BS2
No data are available on observation of this variant in healthy adults to assess whether it occurs in the absence of disease.
BS3
No well-established in vitro or in vivo functional studies demonstrating no damaging effect have been identified for this variant.
BS4
No segregation data are available to assess lack of cosegregation with disease in affected family members.
BP1
Although CDK12 loss-of-function is a supported disease mechanism in germline prostate cancer, missense variants in CDK12 can also be pathogenic (particularly within the kinase domain).
BP2
No data on observation of this variant in trans with a known pathogenic variant in CDK12 are available.
BP5
No data are available on a case harboring this variant with an alternate molecular basis for disease.
BP6
ClinVar classification is Uncertain Significance (1-star), not benign.
N/A · 2
PVS1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.1991e-07; MAF= 0.00006%, 1/1613138 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22856e-05; MAF= 0.00223%, 1/44872 alleles, homozygotes = 0).
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
6.2e-05%
· 1 / 1,613,138
0 hom
0 hom
East Asian 1 / 44,872 |
0.0022% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 3830749)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.104. BayesDel score = -0.261965.
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. CDK12, a cyclin dependent kinase, is recurrently mutated in metastatic prostate and serous ovarian cancers.
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; COSV71000764, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links