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_000546.6(TP53):c.946C>A (p.Pro316Thr)

CA001212

230382 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: f2e706ef-eea4-48c8-917b-970c7c07543c
Approved on: 2025-03-04
Published on: 2025-06-23

HGVS expressions

NM_000546.6:c.946C>A
NM_000546.6(TP53):c.946C>A (p.Pro316Thr)
NC_000017.11:g.7673582G>T
CM000679.2:g.7673582G>T
NC_000017.10:g.7576900G>T
CM000679.1:g.7576900G>T
NC_000017.9:g.7517625G>T
NG_017013.2:g.18969C>A
ENST00000503591.2:c.946C>A
ENST00000508793.6:c.946C>A
ENST00000509690.6:c.550C>A
ENST00000514944.6:c.667C>A
ENST00000604348.6:c.925C>A
ENST00000269305.9:c.946C>A
ENST00000269305.8:c.946C>A
ENST00000359597.8:c.946C>A
ENST00000413465.6:c.782+599C>A
ENST00000420246.6:c.946C>A
ENST00000445888.6:c.946C>A
ENST00000455263.6:c.946C>A
ENST00000504290.5:c.550C>A
ENST00000504937.5:c.550C>A
ENST00000509690.5:c.550C>A
ENST00000510385.5:c.550C>A
ENST00000576024.1:c.6C>A
ENST00000610292.4:c.829C>A
ENST00000610538.4:c.829C>A
ENST00000610623.4:c.469C>A
ENST00000615910.4:c.913C>A
ENST00000617185.4:c.946C>A
ENST00000618944.4:c.469C>A
ENST00000619186.4:c.469C>A
ENST00000619485.4:c.829C>A
ENST00000620739.4:c.829C>A
ENST00000622645.4:c.829C>A
ENST00000635293.1:c.829C>A
NM_000546.5:c.946C>A
NM_001126112.2:c.946C>A
NM_001126113.2:c.946C>A
NM_001126114.2:c.946C>A
NM_001126115.1:c.550C>A
NM_001126116.1:c.550C>A
NM_001126117.1:c.550C>A
NM_001126118.1:c.829C>A
NM_001276695.1:c.829C>A
NM_001276696.1:c.829C>A
NM_001276697.1:c.469C>A
NM_001276698.1:c.469C>A
NM_001276699.1:c.469C>A
NM_001276760.1:c.829C>A
NM_001276761.1:c.829C>A
NM_001276695.2:c.829C>A
NM_001276696.2:c.829C>A
NM_001276697.2:c.469C>A
NM_001276698.2:c.469C>A
NM_001276699.2:c.469C>A
NM_001276760.2:c.829C>A
NM_001276761.2:c.829C>A
NM_001126112.3:c.946C>A
NM_001126113.3:c.946C>A
NM_001126114.3:c.946C>A
NM_001126115.2:c.550C>A
NM_001126116.2:c.550C>A
NM_001126117.2:c.550C>A
NM_001126118.2:c.829C>A
NM_001276695.3:c.829C>A
NM_001276696.3:c.829C>A
NM_001276697.3:c.469C>A
NM_001276698.3:c.469C>A
NM_001276699.3:c.469C>A
NM_001276760.3:c.829C>A
NM_001276761.3:c.829C>A
More

Likely Benign

Met criteria codes 3
BP4 PM2_Supporting BS2_Supporting
Not Met criteria codes 13
PS4 PS3 PS2 PS1 BA1 PP1 PP3 PM1 PM5 PM6 BS3 BS4 BS1

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.3.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6:c.946C>A variant in TP53 is a missense variant predicted to cause substitution of proline by threonine at amino acid 316 (p.Pro316Thr). 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). 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; Internal lab contributor). This variant has an allele frequency of 0.000003098 (5/1614040 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 conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 16007150, 29979965, 30224644). Computational predictor scores (BayesDel = -0.0226052; 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 Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BP4_Moderate. (Bayesian Points: -2; VCEP specifications version 2.3)
Met criteria codes
BP4
BP4_MODERATE Computational predictor scores (BayesDel = -0.0226052; 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).
PM2_Supporting
This variant has an allele frequency of 0.000003098 (5/1614040 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).
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; Internal lab contributor).
Not Met criteria codes
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).
PS3
In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 30224644)
No LOF, 0.5457 PubMed:30224644
Non-functional 12.9% PubMed:12826609
PS2
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
BA1
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
2 different missense variants (p.Pro316Leu, p.Pro316Ser) in the same codon have been reported (ClinVar Variation IDs:528273, 823268). However, these variants have a higher Grantham score than p.Pro316Thr and do not meet criteria for PM5 code application (PM5 not met).
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 16007150, 29979965, 30224644)
No LOF, 0.5457 PubMed:30224644
Non-functional 12.9% PubMed:12826609
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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