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

CA000424

127823 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

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

• Met criteria codes: PS4_Supporting BS3_Supporting PP3

• Not Met criteria codes: BA1 PM5 PM1 BS1 BP4

Expert Panel

TP53 VCEP

Criteria Specification Information

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.

Met criteria codes

• 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
• 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%).
• PP3: Bayesdel is 0.59 and AGVGD is C35.

Not Met criteria codes

• BA1: 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
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline