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 computer assertion could be determined for this classification!

Variant: NM_000546.5(TP53):c.107C>A (p.Pro36Gln)

CA000031

141597 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 6b107a24-eff7-4b60-b98a-3d8682be8658
Approved on: 2024-09-06
Published on: 2024-09-06

HGVS expressions

NM_000546.5:c.107C>A
NM_000546.5(TP53):c.107C>A (p.Pro36Gln)
NC_000017.11:g.7676262G>T
CM000679.2:g.7676262G>T
NC_000017.10:g.7579580G>T
CM000679.1:g.7579580G>T
NC_000017.9:g.7520305G>T
NG_017013.2:g.16289C>A
ENST00000503591.2:c.107C>A
ENST00000508793.6:c.107C>A
ENST00000509690.6:c.-21-1026C>A
ENST00000514944.6:c.96+120C>A
ENST00000604348.6:c.107C>A
ENST00000269305.9:c.107C>A
ENST00000269305.8:c.107C>A
ENST00000359597.8:c.107C>A
ENST00000413465.6:c.107C>A
ENST00000420246.6:c.107C>A
ENST00000445888.6:c.107C>A
ENST00000455263.6:c.107C>A
ENST00000503591.1:c.107C>A
ENST00000505014.5:n.363C>A
ENST00000508793.5:c.107C>A
ENST00000509690.5:c.-21-1026C>A
ENST00000514944.5:c.96+120C>A
ENST00000604348.5:c.107C>A
ENST00000610292.4:c.-11C>A
ENST00000610538.4:c.-11C>A
ENST00000615910.4:c.107C>A
ENST00000617185.4:c.107C>A
ENST00000619485.4:c.-11C>A
ENST00000620739.4:c.-11C>A
ENST00000622645.4:c.-11C>A
ENST00000635293.1:c.-11C>A
NM_001126112.2:c.107C>A
NM_001126113.2:c.107C>A
NM_001126114.2:c.107C>A
NM_001126118.1:c.-11C>A
NM_001276695.1:c.-11C>A
NM_001276696.1:c.-11C>A
NM_001276760.1:c.-11C>A
NM_001276761.1:c.-11C>A
NM_001276695.2:c.-11C>A
NM_001276696.2:c.-11C>A
NM_001276760.2:c.-11C>A
NM_001276761.2:c.-11C>A
NM_000546.6:c.107C>A
NM_001126112.3:c.107C>A
NM_001126113.3:c.107C>A
NM_001126114.3:c.107C>A
NM_001126118.2:c.-11C>A
NM_001276695.3:c.-11C>A
NM_001276696.3:c.-11C>A
NM_001276760.3:c.-11C>A
NM_001276761.3:c.-11C>A
More

Benign

Met criteria codes 4
PM2_Supporting BS3 BS2 BP4
Not Met criteria codes 14
PS1 PS4 PS2 PS3 BA1 PP1 PP4 PP3 PM6 PM1 PM5 BS4 BS1 BP2

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 2.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.107C>A variant in TP53 is a missense variant predicted to cause substitution of proline by glutamine at amino acid 36 (p.Pro36Gln). This variant has been observed in 4-7 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_Moderate; Internal lab contributor: Invitae). 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 = -0.07; 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. Although SpliceAI predicts a weak potential splice effect, expert review suggests that there is no actual impact on the native site, and the variant is therefore considered to have no impact on splicing (BP4_Moderate). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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_Moderate BS3, BP4_Moderate, PM2_Supporting. (Bayesian Points: -7; VCEP specifications version 2.0; 9/6/2024)
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
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).
BS2
BS2_MODERATE BS2_Moderate: This variant has been observed in 4-7 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_Moderate; Internal lab contributor: Invitae).
BP4
BP4_MODERATE Computational predictor scores (BayesDel = -0.07; 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. Although SpliceAI predicts a weak potential splice effect, expert review suggests that there is no actual impact on the native site, and the variant is therefore considered to have no impact on splicing (BP4_Moderate).
Not Met criteria codes
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
This variant received a total of 0.5 points across 1 proband with HER2+ breast cancer under age 40 (PS4 not met; Internal lab contributor: Ambry).
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
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
PP4
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
PM6
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
4 different missense variants (p.Pro75Leu, p.Pro75Thr, p.Pro36Leu, p.Pro36Ser) in the same codon have been reported (ClinVar Variation IDs: 836766, 2003705, 818331, 182921). 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).
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
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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