Variant: NM_000546.5(TP53):c.1060C>A (p.Gln354Lys)

CA000816

231485 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 84fd8478-98b3-4da0-a569-c3ef1e09753e

HGVS expressions

NM_000546.5:c.1060C>A
NM_000546.5(TP53):c.1060C>A (p.Gln354Lys)
NC_000017.11:g.7670649G>T
CM000679.2:g.7670649G>T
NC_000017.10:g.7573967G>T
CM000679.1:g.7573967G>T
NC_000017.9:g.7514692G>T
NG_017013.2:g.21902C>A
ENST00000269305.9:c.1060C>A
ENST00000269305.8:c.1060C>A
ENST00000359597.8:n.993+2886C>A
ENST00000413465.6:n.782+3532C>A
ENST00000420246.6:c.*167C>A
ENST00000445888.6:c.1060C>A
ENST00000455263.6:c.*79C>A
ENST00000504290.5:c.*79C>A
ENST00000504937.5:c.664C>A
ENST00000510385.5:c.*167C>A
ENST00000576024.1:n.54-959C>A
ENST00000610292.4:c.943C>A
ENST00000610538.4:c.*79C>A
ENST00000610623.4:c.*79C>A
ENST00000615910.4:n.1027C>A
ENST00000617185.4:c.*167C>A
ENST00000618944.4:c.*167C>A
ENST00000619186.4:c.583C>A
ENST00000619485.4:c.943C>A
ENST00000620739.4:c.943C>A
ENST00000622645.4:c.*167C>A
ENST00000635293.1:c.943C>A
NM_001126112.2:c.1060C>A
NM_001126113.2:c.*79C>A
NM_001126114.2:c.*167C>A
NM_001126115.1:c.664C>A
NM_001126116.1:c.*167C>A
NM_001126117.1:c.*79C>A
NM_001126118.1:c.943C>A
NM_001276695.1:c.*79C>A
NM_001276696.1:c.*167C>A
NM_001276697.1:c.583C>A
NM_001276698.1:c.*167C>A
NM_001276699.1:c.*79C>A
NM_001276760.1:c.943C>A
NM_001276761.1:c.943C>A
NM_001276695.2:c.*79C>A
NM_001276696.2:c.*167C>A
NM_001276697.2:c.583C>A
NM_001276698.2:c.*167C>A
NM_001276699.2:c.*79C>A
NM_001276760.2:c.943C>A
NM_001276761.2:c.943C>A
NM_000546.6:c.1060C>A
NM_001126112.3:c.1060C>A
NM_001126113.3:c.*79C>A
NM_001126114.3:c.*167C>A
NM_001126115.2:c.664C>A
NM_001126116.2:c.*167C>A
NM_001126117.2:c.*79C>A
NM_001126118.2:c.943C>A
NM_001276695.3:c.*79C>A
NM_001276696.3:c.*167C>A
NM_001276697.3:c.583C>A
NM_001276698.3:c.*167C>A
NM_001276699.3:c.*79C>A
NM_001276760.3:c.943C>A
NM_001276761.3:c.943C>A

Likely Benign

• Met criteria codes: BS3 BP4 BS2_Supporting

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

Expert Panel

TP53 VCEP

Criteria Specification Information

Evidence submitted by expert panel

TP53 VCEP

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). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). This variant has been observed in 4 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributors). In summary, TP53 c.1060C>A (p.Gln354Lys) 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: BS3, BP4, BS2_Supporting.

Met criteria codes

• BS3: BS3: 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) [Giacomelli Nutlin = -0.251972851; Giacomelli Toposide = 0.863742646; Kato Transactivation assay = 123].
• BP4: BP4 (missense variants): This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). [A-GVGD = C0; BayesDel = -0.2829].
• BS2_Supporting: Not in FLOSSIES. Ambry observed in four 60+ year old cancer free females.

Not Met criteria codes

• PS2: 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
• PS4: PMID 24549055 is also listed in IARC: no further information on the proband is found in the article. Authors note only 1 family from the set met Chompret ( Sup Figure S3, which does not include Q354K). Assumed proband does not meet LFS or Chompret. No cases obtained from internal laboratory data. 0.5 points total.
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: 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
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: Variant is present (5/250864 on 11-18-20) in gnomAD.
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: Q354K is not a germline hotspot and not found as a somatic hotspot in cancerhotspots.org
• BA1: 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: 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

Approved on: 2021-08-02

Published on: 2021-09-24