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]
Link to SEPIO compliant JSON-LD document
  • See Evidence submitted by expert panel for details.

Variant: NM_001126112.2(TP53):c.215C>A (p.Pro72His)

CA000071

185120 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 5b6326a9-cfce-4111-96c4-46eaacd8c2df

HGVS expressions

NM_001126112.2:c.215C>A
NM_001126112.2(TP53):c.215C>A (p.Pro72His)
ENST00000269305.9:c.215C>A
ENST00000269305.8:c.215C>A
ENST00000359597.8:n.215C>A
ENST00000413465.6:n.215C>A
ENST00000420246.6:c.215C>A
ENST00000445888.6:c.215C>A
ENST00000455263.6:c.215C>A
ENST00000503591.1:c.215C>A
ENST00000505014.5:n.471C>A
ENST00000508793.5:c.215C>A
ENST00000509690.5:c.-21-918C>A
ENST00000514944.5:c.96+228C>A
ENST00000604348.5:c.215C>A
ENST00000610292.4:c.98C>A
ENST00000610538.4:c.98C>A
ENST00000615910.4:n.215C>A
ENST00000617185.4:c.215C>A
ENST00000619485.4:c.98C>A
ENST00000620739.4:c.98C>A
ENST00000622645.4:c.98C>A
ENST00000635293.1:c.98C>A
NM_000546.5:c.215C>A
NM_001126113.2:c.215C>A
NM_001126114.2:c.215C>A
NM_001126118.1:c.98C>A
NM_001276695.1:c.98C>A
NM_001276696.1:c.98C>A
NM_001276760.1:c.98C>A
NM_001276761.1:c.98C>A
NM_001276695.2:c.98C>A
NM_001276696.2:c.98C>A
NM_001276760.2:c.98C>A
NM_001276761.2:c.98C>A
NM_000546.6:c.215C>A
NM_001126112.3:c.215C>A
NM_001126113.3:c.215C>A
NM_001126114.3:c.215C>A
NM_001126118.2:c.98C>A
NM_001276695.3:c.98C>A
NM_001276696.3:c.98C>A
NM_001276760.3:c.98C>A
NM_001276761.3:c.98C>A
NC_000017.11:g.7676154G>T
CM000679.2:g.7676154G>T
NC_000017.10:g.7579472G>T
CM000679.1:g.7579472G>T
NC_000017.9:g.7520197G>T
NG_017013.2:g.16397C>A

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"
Met criteria codes 4
BP4 BS2_Supporting PM2_Supporting BS3
Not Met criteria codes 13
BP2 PS2 PS4 PS3 PS1 BA1 PP1 PP3 PM6 PM1 PM5 BS4 BS1

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). ). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Transactivation assays show [retained/supertransactivation] 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) Finally, this variant has been observed in 2 60+ year old females without a cancer diagnosis (BS2_Supporting, Invitae internal data). In summary, TP53 c.215C>A; p.Pro72His 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: PM2_supporting, BP4, BS3, BS2_supporting. PM2_Supporting should not be considered conflicting evidence as variant otherwise meets criteria for Likely Benign classification.
Met criteria codes
BP4
Align-GVGD Class C0; BayesDel -0.1017; no splicing effect predicted (varSEAK)
BS2_Supporting
Not identified in FLOSSIES, identified in 2 women (heterozygous) cancer-free at 60 years by Invitae
PM2_Supporting
Absent from gnomAD
BS3
Kato - functional median 86% of wt; Giacomelli p53WT Z-score: -0.147 and p53NULL Etoposide: 0.308 (functional); not DNE; not LOF
Shows transactivation in yeast similar to wild type. PubMed:12826609
Not Met criteria codes
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Not identified in any probands meeting LFS or Chompret criteria in the literature
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
Absent from gnomAD
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
Align-GVGD Class C0; BayesDel -0.1017
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Not a known hotspot
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
Absent from gnomAD
Approved on: 2021-04-19
Published on: 2021-06-16
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