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_000546.5(TP53):c.1151T>C (p.Met384Thr)

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA16615930

406575 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 634ba13c-7c21-4983-bf33-e25d5fc6edad

Approved on: 2025-01-16

Published on: 2025-01-16

HGVS expressions

NM_000546.5:c.1151T>C

NM_000546.5(TP53):c.1151T>C (p.Met384Thr)

NC_000017.11:g.7669640A>G

CM000679.2:g.7669640A>G

NC_000017.10:g.7572958A>G

CM000679.1:g.7572958A>G

NC_000017.9:g.7513683A>G

NG_017013.2:g.22911T>C

ENST00000503591.2:c.1151T>C

ENST00000508793.6:c.1151T>C

ENST00000509690.6:c.755T>C

ENST00000514944.6:c.872T>C

ENST00000604348.6:c.1130T>C

ENST00000269305.9:c.1151T>C

ENST00000269305.8:c.1151T>C

ENST00000359597.8:c.994-3396T>C

ENST00000413465.6:c.782+4541T>C

ENST00000420246.6:c.*258T>C

ENST00000445888.6:c.1151T>C

ENST00000455263.6:c.*170T>C

ENST00000504290.5:c.*170T>C

ENST00000504937.5:c.755T>C

ENST00000510385.5:c.*258T>C

ENST00000576024.1:c.104T>C

ENST00000610292.4:c.1034T>C

ENST00000610538.4:c.*170T>C

ENST00000610623.4:c.*170T>C

ENST00000615910.4:c.1118T>C

ENST00000617185.4:c.*258T>C

ENST00000618944.4:c.*258T>C

ENST00000619186.4:c.674T>C

ENST00000619485.4:c.1034T>C

ENST00000620739.4:c.1034T>C

ENST00000622645.4:c.*258T>C

ENST00000635293.1:c.983+969T>C

NM_001126112.2:c.1151T>C

NM_001126113.2:c.*170T>C

NM_001126114.2:c.*258T>C

NM_001126115.1:c.755T>C

NM_001126116.1:c.*258T>C

NM_001126117.1:c.*170T>C

NM_001126118.1:c.1034T>C

NM_001276695.1:c.*170T>C

NM_001276696.1:c.*258T>C

NM_001276697.1:c.674T>C

NM_001276698.1:c.*258T>C

NM_001276699.1:c.*170T>C

NM_001276760.1:c.1034T>C

NM_001276761.1:c.1034T>C

NM_001276695.2:c.*170T>C

NM_001276696.2:c.*258T>C

NM_001276697.2:c.674T>C

NM_001276698.2:c.*258T>C

NM_001276699.2:c.*170T>C

NM_001276760.2:c.1034T>C

NM_001276761.2:c.1034T>C

NM_000546.6:c.1151T>C

NM_001126112.3:c.1151T>C

NM_001126113.3:c.*170T>C

NM_001126114.3:c.*258T>C

NM_001126115.2:c.755T>C

NM_001126116.2:c.*258T>C

NM_001126117.2:c.*170T>C

NM_001126118.2:c.1034T>C

NM_001276695.3:c.*170T>C

NM_001276696.3:c.*258T>C

NM_001276697.3:c.674T>C

NM_001276698.3:c.*258T>C

NM_001276699.3:c.*170T>C

NM_001276760.3:c.1034T>C

NM_001276761.3:c.1034T>C

Benign

BS2_Supporting BS3 BP4

PS2 PS4 PS3 PS1 PP4 PP1 PP3 PM1 PM5 PM2 BA1 BS4 BS1

Evidence Links 2

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6: c.1151T>C variant in TP53 is a missense variant predicted to cause substitution of methionine by threonine at amino acid 384 (p.Met384Thr). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; PMIDs, ClinVar SCVs, Internal lab contributors). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.121169; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -7; VCEP specifications version 2.0; 1/15/2025)

BS2_Supporting

This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; PMIDs, ClinVar SCVs, Internal lab contributors).

BS3

In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644).

functional PubMed:12826609

noDNE+noLOF PubMed:30224644

BP4

BP4_MODERATE Computational predictor scores (BayesDel = -0.121169; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate).

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

PP4

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

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM1

This variant does not reside within a region of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1 not met).

PM5

The missense variant c.1150A>G, p.Met384Val has been curated as Likely Benign by the TP53 VCEP. 3 different missense variants (p.Met384Ile, p.Met384Arg, p.Met384Leu) in the same codon have been reported (ClinVar Variation IDs: 639734, 458521, 1493091). However, the variants have not yet been curated to determine if they would be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PM5 not evaluated)

PM2

The highest population minor allele frequency in gnomAD v4.1.0 is 0.00006669 (4/59980 alleles) in the Admixed population (PM2, BS1, and BA1 are not met).

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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