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]

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Variant: NM_000546.6(TP53):c.188C>G (p.Ala63Gly)

CA10580957

229693 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome 1

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: e2b86e34-c2dd-4cfe-97f2-92af3ac253cc

HGVS expressions

NM_000546.6:c.188C>G

NM_000546.6(TP53):c.188C>G (p.Ala63Gly)

ENST00000269305.9:c.188C>G

ENST00000269305.8:c.188C>G

ENST00000359597.8:n.188C>G

ENST00000413465.6:n.188C>G

ENST00000420246.6:c.188C>G

ENST00000445888.6:c.188C>G

ENST00000455263.6:c.188C>G

ENST00000503591.1:c.188C>G

ENST00000505014.5:n.444C>G

ENST00000508793.5:c.188C>G

ENST00000509690.5:c.-21-945C>G

ENST00000514944.5:c.96+201C>G

ENST00000604348.5:c.188C>G

ENST00000610292.4:c.71C>G

ENST00000610538.4:c.71C>G

ENST00000615910.4:n.188C>G

ENST00000617185.4:c.188C>G

ENST00000619485.4:c.71C>G

ENST00000620739.4:c.71C>G

ENST00000622645.4:c.71C>G

ENST00000635293.1:c.71C>G

NM_000546.5:c.188C>G

NM_001126112.2:c.188C>G

NM_001126113.2:c.188C>G

NM_001126114.2:c.188C>G

NM_001126118.1:c.71C>G

NM_001276695.1:c.71C>G

NM_001276696.1:c.71C>G

NM_001276760.1:c.71C>G

NM_001276761.1:c.71C>G

NM_001276695.2:c.71C>G

NM_001276696.2:c.71C>G

NM_001276760.2:c.71C>G

NM_001276761.2:c.71C>G

NM_001126112.3:c.188C>G

NM_001126113.3:c.188C>G

NM_001126114.3:c.188C>G

NM_001126118.2:c.71C>G

NM_001276695.3:c.71C>G

NM_001276696.3:c.71C>G

NM_001276760.3:c.71C>G

NM_001276761.3:c.71C>G

NC_000017.11:g.7676181G>C

CM000679.2:g.7676181G>C

NC_000017.10:g.7579499G>C

CM000679.1:g.7579499G>C

NC_000017.9:g.7520224G>C

NG_017013.2:g.16370C>G

Likely Benign

BS3 BP4 BS2_Supporting

BS4 BS1 BP2 PS2 PS4 PS3 PS1 BA1 PP1 PP3 PM1 PM5 PM6 PM2

Evidence Links 0

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

Transactivation assays show retained/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 (BP4). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor). In summary, TP53 c.188C>G (p.Ala63Gly) meets criteria for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, BP4, BS2_Supporting.

BS3

Giacomelli (PMID: 30224644): Nutlin = -0.08558877498; Giacomelli Toposide = 0.456671067; N/A in Kotler: (PMID: 29979965); Kato (PMID: 12826609): Transactivation assay = 75.3. No DNE + No LOF + functional. These assays combine to a BS3 evidence code.

BP4

Fortuno (PMID: 29775997) Align-GVGD Class: C0: Tolerated; Bayes-del: -0.155932;VarSEAK: Class 1 (no splicing effect); ; SpliceAI Δ=0.39 (no effect)

BS2_Supporting

Not found in FLOSSIES database. Two women 60+ with no cancer reported by Ambry: Organization ID: 61756 internal data. One woman 60+ years with no cancer reported by Color: Organization ID: 505849 internal data. No women 60+ with no cancer by GeneDx: Organization ID: 26957 internal data. Three women 60+ with no cancer by Invitae: Organization ID: 500031 internal data.

BS4