Variant: NM_000546.5(TP53):c.364G>A (p.Val122Met)

CA000134

141101 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome 1

Inheritance Mode: Autosomal dominant inheritance

UUID: b798ce06-59db-49cb-9737-d4dd3180f978

Approved on: 2021-06-02

Published on: 2021-06-16

HGVS expressions

NM_000546.5:c.364G>A
NM_000546.5(TP53):c.364G>A (p.Val122Met)
NC_000017.11:g.7676005C>T
CM000679.2:g.7676005C>T
NC_000017.10:g.7579323C>T
CM000679.1:g.7579323C>T
NC_000017.9:g.7520048C>T
NG_017013.2:g.16546G>A
ENST00000269305.9:c.364G>A
ENST00000269305.8:c.364G>A
ENST00000359597.8:n.364G>A
ENST00000413465.6:n.364G>A
ENST00000420246.6:c.364G>A
ENST00000445888.6:c.364G>A
ENST00000455263.6:c.364G>A
ENST00000503591.1:c.364G>A
ENST00000505014.5:n.620G>A
ENST00000508793.5:c.364G>A
ENST00000509690.5:c.-21-769G>A
ENST00000514944.5:c.96+377G>A
ENST00000604348.5:c.364G>A
ENST00000610292.4:c.247G>A
ENST00000610538.4:c.247G>A
ENST00000615910.4:n.340+20G>A
ENST00000617185.4:c.364G>A
ENST00000619485.4:c.247G>A
ENST00000620739.4:c.247G>A
ENST00000622645.4:c.247G>A
ENST00000635293.1:c.247G>A
NM_001126112.2:c.364G>A
NM_001126113.2:c.364G>A
NM_001126114.2:c.364G>A
NM_001126118.1:c.247G>A
NM_001276695.1:c.247G>A
NM_001276696.1:c.247G>A
NM_001276760.1:c.247G>A
NM_001276761.1:c.247G>A
NM_001276695.2:c.247G>A
NM_001276696.2:c.247G>A
NM_001276760.2:c.247G>A
NM_001276761.2:c.247G>A
NM_000546.6:c.364G>A
NM_001126112.3:c.364G>A
NM_001126113.3:c.364G>A
NM_001126114.3:c.364G>A
NM_001126118.2:c.247G>A
NM_001276695.3:c.247G>A
NM_001276696.3:c.247G>A
NM_001276760.3:c.247G>A
NM_001276761.3:c.247G>A

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

• Met criteria codes: BP4 BS3_Supporting BS2_Supporting PM2_Supporting

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

Expert Panel

TP53 VCEP

Criteria Specification Information

Evidence submitted by expert panel

TP53 VCEP

This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). Transactivation assays show a partially functional variant according to Kato, et al. and there are two additional in vitro assays demonstrating retained function (BS3_Supporting; PMID: 12826609, 30224644, 25584008). 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 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Invitae). In summary, TP53 c.364G>A (p.Val122Met) 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: PM2_Supporting, BS3_Supporting, BP4, BS2_Supporting. PM2_Supporting should not be considered conflicting evidence as there is sufficient evidence to classify as Likely Benign.

Met criteria codes

• BP4: aGVGD=C15; BayesDel=0.1341 (evidence of non-pathogenicity)
• BS3_Supporting: Yeast transactivation study (Kato et al.) shows partially retained function. Neither the Giacomelli nor the Kotler assays demonstrate loss of function. However, the GIacomelli assay demonstrates possible dominant negative effect.
• BS2_Supporting: Variant not present in FLOSSIES database. Seen in 3 cancer-free 60+ yo F at Invitae.
• PM2_Supporting: Variant is absent from gnomAD. VCEP uses a supporting level for this code.

Not Met criteria codes

• BA1: Absent from databases.
• BP2: Not reported to co-occur with P/LP variant
• BS4: Segregation information unknown
• BS1: Absent from databases.
• PP1: Segregation information unknown
• PP3: aGVGD=C15; BayesDel=0.1341 (evidence of non-pathogenicity)
• PM6: Not high suspicion of de novo
• PM1: Not in known hot spot codon. Not in cancerhotspots.org.
• PM5: No other known variants in this codon.
• PS2: Not high suspicion of de novo
• PS4: No cases found in the literature or in IARC. Seen at least 20 times in genetic testing laboratories (Invitae, Ambry, Color, Mayo), according to internal data. One individual from Color is known to meet Chompret criteria (0.5 pts according to TP53 VCEP; insufficient to apply code).
• PS3: Yeast transactivation study (Kato et al.) shows partially retained function. Neither the Giacomelli nor the Kotler assays demonstrate loss of function. However, the GIacomelli assay demonstrates possible dominant negative effect.
• PS1: No other known variants in this codon.