Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000546.5(TP53):c.37C>T (p.Pro13Ser)

CA16616008

406604 (ClinVar)

Gene: TP53 (HGNC:7157)
Condition: Li-Fraumeni syndrome (MONDO:0018875)
Inheritance Mode: Autosomal dominant inheritance
UUID: f7698bc5-923c-4132-b1b9-68a6bd158f1b
Approved on: 2026-02-05
Published on: 2026-02-10

HGVS expressions

NM_000546.5(TP53):c.37C>T (p.Pro13Ser)
NM_000546.5:c.37C>T
NC_000017.11:g.7676558G>A
CM000679.2:g.7676558G>A
NC_000017.10:g.7579876G>A
CM000679.1:g.7579876G>A
NC_000017.9:g.7520601G>A
NG_017013.2:g.15993C>T
ENST00000503591.2:c.37C>T
ENST00000508793.6:c.37C>T
ENST00000509690.6:c.-21-1322C>T
ENST00000514944.6:c.37C>T
ENST00000604348.6:c.37C>T
ENST00000269305.9:c.37C>T
ENST00000269305.8:c.37C>T
ENST00000359597.8:c.37C>T
ENST00000413465.6:c.37C>T
ENST00000420246.6:c.37C>T
ENST00000445888.6:c.37C>T
ENST00000455263.6:c.37C>T
ENST00000503591.1:c.37C>T
ENST00000505014.5:n.176C>T
ENST00000508793.5:c.37C>T
ENST00000509690.5:c.-21-1322C>T
ENST00000514944.5:c.37C>T
ENST00000604348.5:c.37C>T
ENST00000610292.4:c.-198C>T
ENST00000610538.4:c.-81C>T
ENST00000615910.4:c.37C>T
ENST00000617185.4:c.37C>T
ENST00000619485.4:c.-81C>T
ENST00000620739.4:c.-81C>T
ENST00000622645.4:c.-81C>T
ENST00000635293.1:c.-81C>T
NM_001126112.2:c.37C>T
NM_001126113.2:c.37C>T
NM_001126114.2:c.37C>T
NM_001126118.1:c.-198C>T
NM_001276695.1:c.-81C>T
NM_001276696.1:c.-81C>T
NM_001276760.1:c.-81C>T
NM_001276761.1:c.-81C>T
NM_001276695.2:c.-81C>T
NM_001276696.2:c.-81C>T
NM_001276760.2:c.-81C>T
NM_001276761.2:c.-81C>T
NM_000546.6:c.37C>T
NM_001126112.3:c.37C>T
NM_001126113.3:c.37C>T
NM_001126114.3:c.37C>T
NM_001126118.2:c.-198C>T
NM_001276695.3:c.-81C>T
NM_001276696.3:c.-81C>T
NM_001276760.3:c.-81C>T
NM_001276761.3:c.-81C>T
More

Uncertain Significance

Met criteria codes 6
PS4_Moderate BS3 BS2_Supporting BP4 PP4 PM2_Supporting
Not Met criteria codes 8
BA1 BS1 PVS1 PS2 PS3 PS1 PP3 PM1

Evidence Links 0

Expert Panel

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.37C>T variant in TP53 is a missense variant predicted to cause substitution of proline by serine at amino acid 13 (p.Pro13Ser). This variant has been reported in 4 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 2 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; 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 has been observed in 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; Internal lab contributor). This variant has an allele frequency of 0.000001239 (2/1613918 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity by the majority of available assays indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 30224644). Computational predictor scores (BayesDel = 0.123287; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -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). Although this variant meets the criteria to be classified as Likely Benign, the VCEP has overridden this classification to variant of uncertain significance for Li Fraumeni syndrome due to conflicting evidence: BS3, BP4, PM2_supporting, PS4_moderate, PP4, BS2_Supporting. (Bayesian Points: -2; VCEP specifications version 2.4)
Met criteria codes
PS4_Moderate
This variant has been reported in 4 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 2 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; Internal lab contributors).
BS3
In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity by the majority of available assays indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 30224644).
BS2_Supporting
This variant has been observed in 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; Internal lab contributor).
BP4
Computational predictor scores (BayesDel = 0.123287; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -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).
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 has an allele frequency of 0.000001239 (2/1613918 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting).
Not Met criteria codes
BA1
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
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
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
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).
Curation History
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