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LYFE SCIENCES
Project: HERA
NM_000546.6:c.722C>A
p.Ser241Tyr  ·  TP53
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Classification rationale
1

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.

cosmic ↗ clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

oncokb ↗ PMID:12826609 ↗ PMID:25584008 ↗
4

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).

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This 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).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Likely pathogenic (1 clinical laboratory).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Loss-of-function.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52713934, n = 54 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueS241
Hotspots ↗