Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000546.5(TP53):c.221C>T (p.Ala74Val)

CA000077

141547 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: ad0ddb25-8464-4d3f-b3c7-c54eb5535e21
Approved on: 2020-08-11
Published on: 2020-08-14

HGVS expressions

NM_000546.5:c.221C>T
NM_000546.5(TP53):c.221C>T (p.Ala74Val)
NC_000017.11:g.7676148G>A
CM000679.2:g.7676148G>A
NC_000017.10:g.7579466G>A
CM000679.1:g.7579466G>A
NC_000017.9:g.7520191G>A
NG_017013.2:g.16403C>T
NM_001126112.2:c.221C>T
NM_001126113.2:c.221C>T
NM_001126114.2:c.221C>T
NM_001126118.1:c.104C>T
NM_001276695.1:c.104C>T
NM_001276696.1:c.104C>T
NM_001276760.1:c.104C>T
NM_001276761.1:c.104C>T
NM_001276695.2:c.104C>T
NM_001276696.2:c.104C>T
NM_001276760.2:c.104C>T
NM_001276761.2:c.104C>T
ENST00000269305.8:c.221C>T
ENST00000359597.8:n.221C>T
ENST00000413465.6:n.221C>T
ENST00000420246.6:c.221C>T
ENST00000445888.6:c.221C>T
ENST00000455263.6:c.221C>T
ENST00000503591.1:c.221C>T
ENST00000505014.5:n.477C>T
ENST00000508793.5:c.221C>T
ENST00000509690.5:c.-21-912C>T
ENST00000514944.5:c.96+234C>T
ENST00000604348.5:c.221C>T
ENST00000610292.4:c.104C>T
ENST00000610538.4:c.104C>T
ENST00000615910.4:n.221C>T
ENST00000617185.4:c.221C>T
ENST00000619485.4:c.104C>T
ENST00000620739.4:c.104C>T
ENST00000622645.4:c.104C>T
ENST00000635293.1:c.104C>T

Likely Benign

Met criteria codes 3
BS3 BS2_Supporting BP4
Not Met criteria codes 16
PVS1 BA1 BS1 BS4 BP7 BP2 PS1 PS3 PS4 PS2 PP3 PP1 PM5 PM4 PM1 PM6

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
Transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). This variant has been observed in >8 60+ year old females without a cancer diagnosis (BS2; Internal laboratory contributor. In summary, TP53 c.221C>T (p.Ala74Val) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3; BP4;BS2_Supporting.
Met criteria codes
BS3
Retained function by Kato (82.8%), and Giacomelli p53WT_Z-score (-0.2148) and Etoposide Z-score (0.7005)
BS2_Supporting
Not identified in FLOSSIES database. Ambry labs has 3 cases cancer free at age 60 (SCV000184950.5).
BP4
functional effect predicted based on align-GVGD (Class C0) and BayesDel (- 0.2135)
Not Met criteria codes
PVS1
Not a null variant
BA1
Allele frequency of 0.00012 in European (Finnish) alleles
BS1
Allele frequency of 0.00012 in European (Finnish) alleles
BS4
No reported data
BP7
Not a synonymous variant
BP2
No reported data
PS1
no other reported variant with same amino acid change
PS3
Kato and Giacomelli predict functional effect
PS4
No cases that meet Classic or Chompret criteria in literature or internal lab data.
PS2
No reported de novo individuals
PP3
functional effect predicted based on align-GVGD (Class C0) and BayesDel (- 0.2135)
PP1
No reported data
PM5
no other missense variant at the same residue have been reported
PM4
Missense variant
PM1
Not located in a mutational hot spot
PM6
No reported de novo individuals
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