Variant: NM_000546.5(TP53):c.322G>A (p.Gly108Ser)

CA000114

142431 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome 1

Inheritance Mode: Autosomal dominant inheritance

UUID: d400b1c5-5b0e-4db7-af65-5d8c17b4a26b

Approved on: 2020-09-01

Published on: 2021-06-16

HGVS expressions

NM_000546.5:c.322G>A
NM_000546.5(TP53):c.322G>A (p.Gly108Ser)
NC_000017.11:g.7676047C>T
CM000679.2:g.7676047C>T
NC_000017.10:g.7579365C>T
CM000679.1:g.7579365C>T
NC_000017.9:g.7520090C>T
NG_017013.2:g.16504G>A
ENST00000503591.2:c.322G>A
ENST00000508793.6:c.322G>A
ENST00000509690.6:c.-21-811G>A
ENST00000514944.6:c.96+335G>A
ENST00000604348.6:c.322G>A
ENST00000269305.9:c.322G>A
ENST00000269305.8:c.322G>A
ENST00000359597.8:c.322G>A
ENST00000413465.6:c.322G>A
ENST00000420246.6:c.322G>A
ENST00000445888.6:c.322G>A
ENST00000455263.6:c.322G>A
ENST00000503591.1:c.322G>A
ENST00000505014.5:n.578G>A
ENST00000508793.5:c.322G>A
ENST00000509690.5:c.-21-811G>A
ENST00000514944.5:c.96+335G>A
ENST00000604348.5:c.322G>A
ENST00000610292.4:c.205G>A
ENST00000610538.4:c.205G>A
ENST00000615910.4:c.322G>A
ENST00000617185.4:c.322G>A
ENST00000619485.4:c.205G>A
ENST00000620739.4:c.205G>A
ENST00000622645.4:c.205G>A
ENST00000635293.1:c.205G>A
NM_001126112.2:c.322G>A
NM_001126113.2:c.322G>A
NM_001126114.2:c.322G>A
NM_001126118.1:c.205G>A
NM_001276695.1:c.205G>A
NM_001276696.1:c.205G>A
NM_001276760.1:c.205G>A
NM_001276761.1:c.205G>A
NM_001276695.2:c.205G>A
NM_001276696.2:c.205G>A
NM_001276760.2:c.205G>A
NM_001276761.2:c.205G>A
NM_000546.6:c.322G>A
NM_001126112.3:c.322G>A
NM_001126113.3:c.322G>A
NM_001126114.3:c.322G>A
NM_001126118.2:c.205G>A
NM_001276695.3:c.205G>A
NM_001276696.3:c.205G>A
NM_001276760.3:c.205G>A
NM_001276761.3:c.205G>A

Likely Benign

• Met criteria codes: BS3_Supporting BP4 BS2_Supporting

• Not Met criteria codes: BS1 BS4 BP5 BP1 BP2 PM1 PM3 PM5 PM6 PM2 PS1 PS2 PS3 PS4 PP1 PP2 PP3 PP4 BA1

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 C0 or Class C15 (BP4). Transactivation assays show a 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). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributors). In summary, TP53 c.322G>A (p.Gly108Ser) 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: BP4, BS3_supporting, BS2_supporting.

Met criteria codes

• BS3_Supporting: Partially functional (Kato) , noDNE & noLOF (Giacomelli), no LOF (Kotler)
• BP4: Align GVGD Class C0, BayesDel 0.0347452, no predicted splicing effect (varseak, spliceAI)
• BS2_Supporting: 3 cases cancer free females at age 60+ years from Ambry internal data, 1 case from Color internal data, 6 cases from Invitae

Not Met criteria codes

• BS1: 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
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: Not in a hotspot codon, not in cancerhotspots.org
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: One VUS at same codon in ClinVar
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: Present in 3 alleles in gnomAD v2.1.1
• PS1: 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
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: Seen in 1/765 osteosarcoma patients unselected for FHx (no details about FHx or age of dx available) PMID: 25896519 1 case meeting Chompret criteria from Ambry internal data (PHx BC <31yo & FHx BC)
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline