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_001126112.2(TP53):c.431A>T (p.Gln144Leu)

CA16603064

376647 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: 14f7870e-291f-4048-9e44-f21278f51581
Approved on: 2024-08-05
Published on: 2024-08-05

HGVS expressions

NM_001126112.2:c.431A>T
NM_001126112.2(TP53):c.431A>T (p.Gln144Leu)
NC_000017.11:g.7675181T>A
CM000679.2:g.7675181T>A
NC_000017.10:g.7578499T>A
CM000679.1:g.7578499T>A
NC_000017.9:g.7519224T>A
NG_017013.2:g.17370A>T
ENST00000503591.2:c.431A>T
ENST00000508793.6:c.431A>T
ENST00000509690.6:c.35A>T
ENST00000514944.6:c.152A>T
ENST00000604348.6:c.410A>T
ENST00000269305.9:c.431A>T
ENST00000269305.8:c.431A>T
ENST00000359597.8:c.431A>T
ENST00000413465.6:c.431A>T
ENST00000420246.6:c.431A>T
ENST00000445888.6:c.431A>T
ENST00000455263.6:c.431A>T
ENST00000504290.5:c.35A>T
ENST00000504937.5:c.35A>T
ENST00000505014.5:n.687A>T
ENST00000508793.5:c.431A>T
ENST00000509690.5:c.35A>T
ENST00000510385.5:c.35A>T
ENST00000514944.5:c.152A>T
ENST00000604348.5:c.410A>T
ENST00000610292.4:c.314A>T
ENST00000610538.4:c.314A>T
ENST00000610623.4:c.-47A>T
ENST00000615910.4:c.398A>T
ENST00000617185.4:c.431A>T
ENST00000618944.4:c.-47A>T
ENST00000619186.4:c.-47A>T
ENST00000619485.4:c.314A>T
ENST00000620739.4:c.314A>T
ENST00000622645.4:c.314A>T
ENST00000635293.1:c.314A>T
NM_000546.5:c.431A>T
NM_001126113.2:c.431A>T
NM_001126114.2:c.431A>T
NM_001126115.1:c.35A>T
NM_001126116.1:c.35A>T
NM_001126117.1:c.35A>T
NM_001126118.1:c.314A>T
NM_001276695.1:c.314A>T
NM_001276696.1:c.314A>T
NM_001276697.1:c.-47A>T
NM_001276698.1:c.-47A>T
NM_001276699.1:c.-47A>T
NM_001276760.1:c.314A>T
NM_001276761.1:c.314A>T
NM_001276695.2:c.314A>T
NM_001276696.2:c.314A>T
NM_001276697.2:c.-47A>T
NM_001276698.2:c.-47A>T
NM_001276699.2:c.-47A>T
NM_001276760.2:c.314A>T
NM_001276761.2:c.314A>T
NM_000546.6:c.431A>T
NM_001126112.3:c.431A>T
NM_001126113.3:c.431A>T
NM_001126114.3:c.431A>T
NM_001126115.2:c.35A>T
NM_001126116.2:c.35A>T
NM_001126117.2:c.35A>T
NM_001126118.2:c.314A>T
NM_001276695.3:c.314A>T
NM_001276696.3:c.314A>T
NM_001276697.3:c.-47A>T
NM_001276698.3:c.-47A>T
NM_001276699.3:c.-47A>T
NM_001276760.3:c.314A>T
NM_001276761.3:c.314A>T
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Uncertain Significance

Met criteria codes 4
PM5_Supporting PM1_Supporting BS3_Supporting PM2_Supporting
Not Met criteria codes 11
PS2 PS1 PS4 PS3 PP1 PP4 PP3 BA1 BS4 BS1 BP4

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.431A>T variant in TP53 is a missense variant predicted to cause substitution of Glutamine by Leucine at amino acid 144 (p.Gln144Leu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity, indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). The results from the computational predictors BayesDel and AlignGVGD do not agree, providing no evidence that correlates with a damaging or benign impact on TP53 function via protein change. Additionally, the computational splicing predictor SpliceAI gives a score of 0.00, predicting that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met). Another missense variant with equal or lesser predicted impact c.431A>C (p.Gln144Pro) (ClinVar Variation ID: 186594), in the same codon has been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications (PM5_Supporting). This variant has 2 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). Due to conflicting evidence, this variant is classified as a variant of unknown significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3_Supporting, PM2_Supporting, PM5_Supporting, PM1_Supporting. (Bayesian Points: 2; VCEP specifications version 2.0; 7/24/2024)
Met criteria codes
PM5_Supporting
Another missense variant c.431A>C (p.Gln144Pro) (ClinVar Variation ID: 186594), in the same codon has been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications (PM5_Supporting). Grantham: Q>L=113; (Q>H=24; Q>R=43; Q>P=76) Q144P: PS3, PM2_Supporting, PM1_Supporting. PP3 not met. Ambry and Invitae have submissions - internal clinical data not requested. LP with current codes. Lit search revealed only tumor sequencing/somatic publications (e.g., PMIDs: 25634010, 11358831, 29079597). Q144H and Q144R: Not likely to reach P/LP. Curation not performed.
PM1_Supporting
This variant has 2 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).
BS3_Supporting
In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity, indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
Not Met criteria codes
PS2
This variant has been identified as a de novo occurrence with unconfirmed parental relationships in an individual with adrenal neuroblastoma; however, no points were applied due to high suspicion of another genetic cancer predisposition variant that could be segregating in the family. (PMID: 12076704).
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
This variant was seen in an individual with adrenal neuroblastoma; however, two additional family members with sarcoma and/or ACC were determined NOT to carry the variant (PMID: 12076704). Because of non-segregation, this classical LFS family does not contribute points to PS4 proband counting.
PS3
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
The results from the computational predictors BayesDel and AlignGVGD do not agree, providing no evidence that correlates with a damaging or benign impact on TP53 function via protein change. Additionally, the computational splicing predictor SpliceAI gives a score of 0.00, predicting that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met). BayesDel = 0.3196; AGVGD = C0
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
This variant has been reported not to segregate with adrenocortical carcinoma and chondrosarcoma in 2 affected family members from 1 family. However, the variant was shown to be de novo, so BS4 is not applied. (PMID: 12076704).
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
The results from the computational predictors BayesDel and AlignGVGD do not agree, providing no evidence that correlates with a damaging or benign impact on TP53 function via protein change. Additionally, the computational splicing predictor SpliceAI gives a score of 0.00, predicting that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met). BayesDel = 0.3196; AGVGD = C0
Curation History
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