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]

Variant: NM_000546.6(TP53):c.396G>C (p.Lys132Asn)

CA16603044

376624 (ClinVar)

Gene: TP53 (HGNC:7157)

Condition: Li-Fraumeni syndrome (MONDO:0018875)

Inheritance Mode: Autosomal dominant inheritance

UUID: d817c4c8-1df0-4998-acec-3488a11fc4b0

Approved on: 2026-09-22

Published on: 2026-09-22

HGVS expressions

NM_000546.6(TP53):c.396G>C (p.Lys132Asn)

NM_000546.6:c.396G>C

NC_000017.11:g.7675216C>G

CM000679.2:g.7675216C>G

NC_000017.10:g.7578534C>G

CM000679.1:g.7578534C>G

NC_000017.9:g.7519259C>G

NG_017013.2:g.17335G>C

ENST00000503591.2:c.396G>C

ENST00000508793.6:c.396G>C

ENST00000509690.6:c.-1G>C

ENST00000514944.6:c.117G>C

ENST00000604348.6:c.376-1G>C

ENST00000269305.9:c.396G>C

ENST00000269305.8:c.396G>C

ENST00000359597.8:c.396G>C

ENST00000413465.6:c.396G>C

ENST00000420246.6:c.396G>C

ENST00000445888.6:c.396G>C

ENST00000455263.6:c.396G>C

ENST00000504290.5:c.-1G>C

ENST00000504937.5:c.-1G>C

ENST00000505014.5:n.652G>C

ENST00000508793.5:c.396G>C

ENST00000509690.5:c.-1G>C

ENST00000510385.5:c.-1G>C

ENST00000514944.5:c.117G>C

ENST00000604348.5:c.376-1G>C

ENST00000610292.4:c.279G>C

ENST00000610538.4:c.279G>C

ENST00000610623.4:c.-82G>C

ENST00000615910.4:c.363G>C

ENST00000617185.4:c.396G>C

ENST00000618944.4:c.-82G>C

ENST00000619186.4:c.-82G>C

ENST00000619485.4:c.279G>C

ENST00000620739.4:c.279G>C

ENST00000622645.4:c.279G>C

ENST00000635293.1:c.279G>C

NM_000546.5:c.396G>C

NM_001126112.2:c.396G>C

NM_001126113.2:c.396G>C

NM_001126114.2:c.396G>C

NM_001126115.1:c.-1G>C

NM_001126116.1:c.-1G>C

NM_001126117.1:c.-1G>C

NM_001126118.1:c.279G>C

NM_001276695.1:c.279G>C

NM_001276696.1:c.279G>C

NM_001276697.1:c.-82G>C

NM_001276698.1:c.-82G>C

NM_001276699.1:c.-82G>C

NM_001276760.1:c.279G>C

NM_001276761.1:c.279G>C

NM_001276695.2:c.279G>C

NM_001276696.2:c.279G>C

NM_001276697.2:c.-82G>C

NM_001276698.2:c.-82G>C

NM_001276699.2:c.-82G>C

NM_001276760.2:c.279G>C

NM_001276761.2:c.279G>C

NM_001126112.3:c.396G>C

NM_001126113.3:c.396G>C

NM_001126114.3:c.396G>C

NM_001126115.2:c.-1G>C

NM_001126116.2:c.-1G>C

NM_001126117.2:c.-1G>C

NM_001126118.2:c.279G>C

NM_001276695.3:c.279G>C

NM_001276696.3:c.279G>C

NM_001276697.3:c.-82G>C

NM_001276698.3:c.-82G>C

NM_001276699.3:c.-82G>C

NM_001276760.3:c.279G>C

NM_001276761.3:c.279G>C

Pathogenic

PP4_Moderate PP3_Moderate PS3 PM1 PM2_Supporting

BP2 BP4 BS2 BS4 BS3 BS1 PP1 PS2 PS4 PS1 BA1 PM6 PM5

Evidence Links 0

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.4

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6: c.396G>C variant in TP53 is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 132 (p.Lys132Asn). This variant received a total of 0.5 points across 1 proband (PS4 not met; Internal lab contributors). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity by the majority of available assays indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965, 39774325). Computational predictor scores (BayesDel = 0.3138; Align GVGD = Class 65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). This variant has 30 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369) (PM1). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PP4_Moderate, PM2_Supporting, PS3, PP3_Moderate, PM1. (Bayesian Points: 11; VCEP specifications version 2.4)

PP4_Moderate

At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors).

PP3_Moderate

Computational predictor scores (BayesDel = 0.3138; Align GVGD = Class 65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate).

PS3

In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity by the majority of available assays indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965, 39774325).

PM1

This variant has 30 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369) (PM1).

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

BP2

No reported incidences.

BP4