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.379T>C (p.Ser127Pro)

CA397843917

934410 (ClinVar)

Gene: TP53 (HGNC:7157)

Condition: Li-Fraumeni syndrome (MONDO:0018875)

Inheritance Mode: Autosomal dominant inheritance

UUID: 130cd553-8ab6-4a2a-8452-d95fd366c6e5

Approved on: 2026-03-04

Published on: 2026-04-22

HGVS expressions

NM_000546.6(TP53):c.379T>C (p.Ser127Pro)

NM_000546.6:c.379T>C

NC_000017.11:g.7675233A>G

CM000679.2:g.7675233A>G

NC_000017.10:g.7578551A>G

CM000679.1:g.7578551A>G

NC_000017.9:g.7519276A>G

NG_017013.2:g.17318T>C

ENST00000503591.2:c.379T>C

ENST00000508793.6:c.379T>C

ENST00000509690.6:c.-18T>C

ENST00000514944.6:c.100T>C

ENST00000604348.6:c.376-18T>C

ENST00000269305.9:c.379T>C

ENST00000269305.8:c.379T>C

ENST00000359597.8:c.379T>C

ENST00000413465.6:c.379T>C

ENST00000420246.6:c.379T>C

ENST00000445888.6:c.379T>C

ENST00000455263.6:c.379T>C

ENST00000503591.1:c.379T>C

ENST00000504290.5:c.-18T>C

ENST00000504937.5:c.-18T>C

ENST00000505014.5:n.635T>C

ENST00000508793.5:c.379T>C

ENST00000509690.5:c.-18T>C

ENST00000510385.5:c.-18T>C

ENST00000514944.5:c.100T>C

ENST00000604348.5:c.376-18T>C

ENST00000610292.4:c.262T>C

ENST00000610538.4:c.262T>C

ENST00000610623.4:c.-99T>C

ENST00000615910.4:c.346T>C

ENST00000617185.4:c.379T>C

ENST00000618944.4:c.-99T>C

ENST00000619186.4:c.-99T>C

ENST00000619485.4:c.262T>C

ENST00000620739.4:c.262T>C

ENST00000622645.4:c.262T>C

ENST00000635293.1:c.262T>C

NM_000546.5:c.379T>C

NM_001126112.2:c.379T>C

NM_001126113.2:c.379T>C

NM_001126114.2:c.379T>C

NM_001126115.1:c.-18T>C

NM_001126116.1:c.-18T>C

NM_001126117.1:c.-18T>C

NM_001126118.1:c.262T>C

NM_001276695.1:c.262T>C

NM_001276696.1:c.262T>C

NM_001276697.1:c.-99T>C

NM_001276698.1:c.-99T>C

NM_001276699.1:c.-99T>C

NM_001276760.1:c.262T>C

NM_001276761.1:c.262T>C

NM_001276695.2:c.262T>C

NM_001276696.2:c.262T>C

NM_001276697.2:c.-99T>C

NM_001276698.2:c.-99T>C

NM_001276699.2:c.-99T>C

NM_001276760.2:c.262T>C

NM_001276761.2:c.262T>C

NM_001126112.3:c.379T>C

NM_001126113.3:c.379T>C

NM_001126114.3:c.379T>C

NM_001126115.2:c.-18T>C

NM_001126116.2:c.-18T>C

NM_001126117.2:c.-18T>C

NM_001126118.2:c.262T>C

NM_001276695.3:c.262T>C

NM_001276696.3:c.262T>C

NM_001276697.3:c.-99T>C

NM_001276698.3:c.-99T>C

NM_001276699.3:c.-99T>C

NM_001276760.3:c.262T>C

NM_001276761.3:c.262T>C

Likely Pathogenic

PM1_Supporting PS3 PP3_Moderate PP4 PM2_Supporting

PS4 PS1 PS2 BP4 PP1 BA1 PM5 BS2 BS4 BS3 BS1

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 2.4.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6(TP53):c.379T>C variant in TP53 is a missense variant predicted to cause substitution of serine by proline at amino acid 127 (p.Ser127Pro). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; Internal lab contributors). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributor). 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 = 0.58628; Align GVGD = Class C65) 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 4 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 (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PP4, PS3, PP3_moderate, PM1_supporting, PM2_supporting. (Bayesian Points: 9; VCEP specifications version 2.4)

PM1_Supporting

This variant has 4 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 (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting).

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).

PP3_Moderate

Computational predictor scores (BayesDel = 0.58628; Align GVGD = Class C65) 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).

PP4

At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributor).

PM2_Supporting

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

PS4

Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; Internal lab contributors).

PS1