Variant: NM_001126112.2(TP53):c.188C>T (p.Ala63Val)

CA000063

182922 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome 1

Inheritance Mode: Autosomal dominant inheritance

UUID: ef9d90c6-8b7a-4989-9f0f-7bd7f52113b0

HGVS expressions

NM_001126112.2:c.188C>T
NM_001126112.2(TP53):c.188C>T (p.Ala63Val)
NC_000017.11:g.7676181G>A
CM000679.2:g.7676181G>A
NC_000017.10:g.7579499G>A
CM000679.1:g.7579499G>A
NC_000017.9:g.7520224G>A
NG_017013.2:g.16370C>T
ENST00000269305.9:c.188C>T
ENST00000269305.8:c.188C>T
ENST00000359597.8:n.188C>T
ENST00000413465.6:n.188C>T
ENST00000420246.6:c.188C>T
ENST00000445888.6:c.188C>T
ENST00000455263.6:c.188C>T
ENST00000503591.1:c.188C>T
ENST00000505014.5:n.444C>T
ENST00000508793.5:c.188C>T
ENST00000509690.5:c.-21-945C>T
ENST00000514944.5:c.96+201C>T
ENST00000604348.5:c.188C>T
ENST00000610292.4:c.71C>T
ENST00000610538.4:c.71C>T
ENST00000615910.4:n.188C>T
ENST00000617185.4:c.188C>T
ENST00000619485.4:c.71C>T
ENST00000620739.4:c.71C>T
ENST00000622645.4:c.71C>T
ENST00000635293.1:c.71C>T
NM_000546.5:c.188C>T
NM_001126113.2:c.188C>T
NM_001126114.2:c.188C>T
NM_001126118.1:c.71C>T
NM_001276695.1:c.71C>T
NM_001276696.1:c.71C>T
NM_001276760.1:c.71C>T
NM_001276761.1:c.71C>T
NM_001276695.2:c.71C>T
NM_001276696.2:c.71C>T
NM_001276760.2:c.71C>T
NM_001276761.2:c.71C>T
NM_000546.6:c.188C>T
NM_001126112.3:c.188C>T
NM_001126113.3:c.188C>T
NM_001126114.3:c.188C>T
NM_001126118.2:c.71C>T
NM_001276695.3:c.71C>T
NM_001276696.3:c.71C>T
NM_001276760.3:c.71C>T
NM_001276761.3:c.71C>T

Likely Benign

• Met criteria codes: BS2_Supporting BS3 BP4

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

Expert Panel

TP53 VCEP

Criteria Specification Information

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 been observed in 2 60+ year old females without a cancer diagnosis (BS2_Supporting: internal laboratory contributor (SCV000545312.6). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). In summary, TP53 c.188C>T (p.Ala63Val) 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, BS2, BP4.

Met criteria codes

• BS2_Supporting: Invitae has two cases of women unaffected 60+ (SCV000545312.6).
• BS3: Present in Kato (81 = Functional)/p53WTNutlin3 Z-score < 0.61 (-0,41953775) and Etoposide Z-score > -0.21 (0,425104211)
• BP4: MET - Align GVGD Class C0; BayesDel = -0.0987. Missense: aGVGD (zebrafish; Class C0 or C15 is considered evidence of non-pathogenicity) and BayesDel <0.16 is considered evidence on non-pathogenicity

Not Met criteria codes

• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: 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
• PS1: 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: Not met - Align GVGD Class C0; BayesDel = -0.0987
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: Not met - Allele count =3; gnomAD = 0,001%
• PM1: Not present in CANCERHOTSPOT
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: Not met - Allele count =3; gnomAD = 0,001%
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: Not met - Allele count =3; gnomAD = 0,001%
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2021-04-12

Published on: 2021-10-11