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.364G>A (p.Val122Met)

CA000134

141101 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome 1

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

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

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"

BS2_Supporting PM2_Supporting BS3_Supporting BP4

PS2 PS4 PS3 PS1 PP1 PP3 BA1 PM1 PM5 BS4 BS1 PM6 BP2

Evidence Links 0

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

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.

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.

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.

BP4

aGVGD=C15; BayesDel=0.1341 (evidence of non-pathogenicity)

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

PS1

No other known variants in this codon.

PP1

Segregation information unknown

PP3

aGVGD=C15; BayesDel=0.1341 (evidence of non-pathogenicity)

BA1

Absent from databases.

PM1

Not in known hot spot codon. Not in cancerhotspots.org.

PM5

No other known variants in this codon.

BS4

Segregation information unknown

BS1

Absent from databases.

PM6

Not high suspicion of de novo

BP2

Not reported to co-occur with P/LP variant

Approved on: 2021-06-02

Published on: 2021-06-16

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