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.800G>A (p.Arg267Gln)

CA000424

127823 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: ca16e21b-853c-433e-88e5-601b2de6c525

Approved on: 2020-08-11

Published on: 2020-08-14

HGVS expressions

NM_000546.5:c.800G>A

NM_000546.5(TP53):c.800G>A (p.Arg267Gln)

NC_000017.11:g.7673820C>T

CM000679.2:g.7673820C>T

NC_000017.10:g.7577138C>T

CM000679.1:g.7577138C>T

NC_000017.9:g.7517863C>T

NG_017013.2:g.18731G>A

NM_001126112.2:c.800G>A

NM_001126113.2:c.800G>A

NM_001126114.2:c.800G>A

NM_001126115.1:c.404G>A

NM_001126116.1:c.404G>A

NM_001126117.1:c.404G>A

NM_001126118.1:c.683G>A

NM_001276695.1:c.683G>A

NM_001276696.1:c.683G>A

NM_001276697.1:c.323G>A

NM_001276698.1:c.323G>A

NM_001276699.1:c.323G>A

NM_001276760.1:c.683G>A

NM_001276761.1:c.683G>A

NM_001276695.2:c.683G>A

NM_001276696.2:c.683G>A

NM_001276697.2:c.323G>A

NM_001276698.2:c.323G>A

NM_001276699.2:c.323G>A

NM_001276760.2:c.683G>A

NM_001276761.2:c.683G>A

ENST00000269305.8:c.800G>A

ENST00000359597.8:n.800G>A

ENST00000413465.6:n.782+361G>A

ENST00000420246.6:c.800G>A

ENST00000445888.6:c.800G>A

ENST00000455263.6:c.800G>A

ENST00000504290.5:c.404G>A

ENST00000504937.5:c.404G>A

ENST00000509690.5:c.404G>A

ENST00000510385.5:c.404G>A

ENST00000610292.4:c.683G>A

ENST00000610538.4:c.683G>A

ENST00000610623.4:c.323G>A

ENST00000615910.4:n.767G>A

ENST00000617185.4:c.800G>A

ENST00000618944.4:c.323G>A

ENST00000619186.4:c.323G>A

ENST00000619485.4:c.683G>A

ENST00000620739.4:c.683G>A

ENST00000622645.4:c.683G>A

ENST00000635293.1:c.683G>A

Uncertain Significance

BS3_Supporting PP3 PS4_Supporting

BP4 PM5 PM1 BA1 BS1

Evidence Links 8

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). This variant has been reported in 2 probands meeting Chrompret criteria (PS4_Supporting; PMID:25584008, internal laboratory contributor). Transactivation assays show partially functional variant 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_Supporting; PMID: 12826609, 30224644). In summary, the clinical significance of TP53 c.800G>A (p.Arg267Gln) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Expert Panel: PP3, PS4_Supporting, BS3_Supporting.

BS3_Supporting

This technically meets the BS_3 supporting criteria, with partially functional transactivation and no evidence of DNE or loss of growth suppression. However, some of the transactivation values from Kato are lower than 20% (the median is 21%).

Mean residual transactivation activity from 4 response elements in yeast is 39%. No DN activity observed. PubMed:21343334

Transactivation assays in H1299 cells show activity similar to WT, and colony reduction assays look similar to WT. PubMed:25584008

DN score of 0.4 (not dominant negative) and Etoposide score of -0.01 (no loss of growth suppression). PubMed:30224644

Partially functional yeast transactivation. Median activation of 21.45% of WT PubMed:12826609

RFS score of -1.27 - no loss of growth suppression PubMed:29979965

PP3

Bayesdel is 0.59 and AGVGD is C35.

PS4_Supporting

Several literature reports, only one meets Chompret criteria for 0.5 points. Two literature reports where proband meets LFS or Chompret but also identified with other TP53 alterations – therefore were not counted. Two internal families from NCI – one family meets Chompret criteria. A second family would theoretically meet Chompret with history of breast, brain, STS, kidney, and other cancers, but also segregating a FH mutation so not used. 0.5+0.5 = 1 point

PubMed:1562462

PubMed:25584008

PubMed:27210295

PubMed:10435620

BP4

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

PM5

No other variants at this position have been evaluated by the TP53 VCEP, but there are two other variants at this location that appear to be pathogenic. p.R267W and p.R267P - However, both of these variants have higher Grantham (101 and 103) than this alteration (43)

PM1

Not in one of the 6 hotspot codons, and only seen 4 times in cancerhotspots.org

BA1

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

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