Evidence Repository - Clinical Genome Resources

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

Variant: NM_000546.5(TP53):c.139C>T (p.Pro47Ser)

CA000053

43588 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: d9f1afe3-5f5c-4af4-8f96-d83399ee9404

HGVS expressions

NM_000546.5:c.139C>T

NM_000546.5(TP53):c.139C>T (p.Pro47Ser)

NC_000017.11:g.7676230G>A

CM000679.2:g.7676230G>A

NC_000017.10:g.7579548G>A

CM000679.1:g.7579548G>A

NC_000017.9:g.7520273G>A

NG_017013.2:g.16321C>T

NM_001126112.2:c.139C>T

NM_001126113.2:c.139C>T

NM_001126114.2:c.139C>T

NM_001126118.1:c.22C>T

NM_001276695.1:c.22C>T

NM_001276696.1:c.22C>T

NM_001276760.1:c.22C>T

NM_001276761.1:c.22C>T

ENST00000269305.8:c.139C>T

ENST00000359597.8:n.139C>T

ENST00000413465.6:n.139C>T

ENST00000420246.6:c.139C>T

ENST00000445888.6:c.139C>T

ENST00000455263.6:c.139C>T

ENST00000503591.1:c.139C>T

ENST00000505014.5:n.395C>T

ENST00000508793.5:c.139C>T

ENST00000509690.5:c.-21-994C>T

ENST00000514944.5:c.96+152C>T

ENST00000604348.5:c.139C>T

ENST00000610292.4:c.22C>T

ENST00000610538.4:c.22C>T

ENST00000615910.4:n.139C>T

ENST00000617185.4:c.139C>T

ENST00000619485.4:c.22C>T

ENST00000620739.4:c.22C>T

ENST00000622645.4:c.22C>T

ENST00000635293.1:c.22C>T

Benign

BP4 BA1 BS2 BS3

PS3 PP3 BS1

Evidence Links 2

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

This variant has a minor allele frequency of 0.01645 (1.6%, 410/24,922 alleles) in the African subpopulation of the gnomAD cohort (BA1). The variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, transactivation assays show 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 at least 105 60+ year old females without a cancer diagnosis (BS2; FLOSSIES database - https://whi.color.com). In summary, TP53 c.139C>T; p.Pro47Ser meets criteria to be classified as benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BA1, BP4, BS3, BS2.

BP4

BayesDel and AGVGD are concordant

BA1

MAF = 1.6% In African population with 393 alleles

BS2

Variant observed in 105 individuals from the FLOSSIES data.

BS3

Supertrans variant in T-A assays; no evidence of DNE or LOF in Giacomelli, et al data

No evidence of DNE or LOF in Giacomelli, et al data PubMed:30224644

Mouse model and human cell lines with the P47S variant reported showing a modest decrease in apoptosis in response to genotoxic stress compared with wildtype. However, given the overwhelming evidence that this variant is a benign germline variant and lack of replication studies, we did not count this evidence. PubMed:27034505

PS3

Given the overwhelming evidence that this variant is a benign germline variant and lack of replication studies, we did not count this evidence.

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2019-08-28

Published on: 2020-01-24

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