The TP53 NM_000546.6:c.722C>A (p.Ser241Tyr, p.S241Y) variant has been observed in somatic cancers in COSMIC (COSV52713934, 54 occurrences) and has been reported in ClinVar as Pathogenic by 4 clinical laboratories and Likely Pathogenic by 1 clinical laboratory.1 This variant is absent from gnomAD v2.1 and has 0/1,613,928 alleles in gnomAD v4.1, which is below the TP53 VCEP PM2_Supporting threshold of 0.00003.2 TP53 VCEP functional data support loss of p53 function for p.Ser241Tyr, with non-functional Kato results and loss of function in the majority of other eligible assays, supporting PS3.3 TP53-specific in silico evidence supports a deleterious effect, with Align-GVGD Class C65, BayesDel 0.544682, a pre-assigned PP3_moderate code, and SpliceAI showing no significant predicted splice impact (max delta score 0.01).4
TP53
Final classification
Likely Pathogenic
TP53 c.722C>A · p.Ser241Tyr
TP53
The TP53 NM_000546.6:c.722C>A (p.Ser241Tyr, p.S241Y) variant has been observed in somatic cancers in COSMIC (COSV52713934, 54 occurrences) and has been reported in ClinVar as Pathogenic by 4 clinical laboratories and Likely Pathogenic by 1 clinical laboratory.
Official TP53 VCEP/CSPEC v2.4.0 point-based final-classification framework (Tavtigian et al., 2020 Bayesian adaptation of ACMG/AMP) was applied to the adjudicated criteria.
Classification rationale
PS3PM2PP3
Likely Pathogenic
TP53 c.722C>A
PS3 + PM2 + PP3
→
Likely Pathogenic
3
vcep_f_u_n_c_t_i_o_n_a_l___w_o_r_k_s_h_e_e_toncokb ↗PMID:12826609 ↗PMID:29979965PMID:30224644PMID:25584008 ↗
4
vcep_p_p_3___b_p_4___c_o_d_e_sspliceai ↗
Gene diagram
· NM_000546.6 · variants mapped to exon structure
TP53
NM_000546.6
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 · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1613928 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74982 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / 1,613,928
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, 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.
ClinVar
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Likely pathogenic (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Loss-of-function.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52713934, n = 54 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
6papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Understanding the function-structure and function-mutation relationships of p53
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Prevalence and spectrum of germline mutations of the p53 gene among patients wit
Found
Structured finding pending for this record — see source link.
Applied to
→PP3 supports · met
Prevalence and functional consequence of TP53 mutations in pediatric adrenocorti
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Allele-specific wild-type TP53 expression in the unaffected carrier parent of ch
Found
Structured finding pending for this record — see source link.
Applied to
→PP3 supports · met
PMID 29979965
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
PMID 30224644
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links