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.393C>A (p.Asn131Lys)

CA002656

246429 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 3147e5cd-492f-4b46-9227-de2572c8bc19
Approved on: 2025-02-06
Published on: 2025-02-07

HGVS expressions

NM_000546.5:c.393C>A
NM_000546.5(TP53):c.393C>A (p.Asn131Lys)
NC_000017.11:g.7675219G>T
CM000679.2:g.7675219G>T
NC_000017.10:g.7578537G>T
CM000679.1:g.7578537G>T
NC_000017.9:g.7519262G>T
NG_017013.2:g.17332C>A
ENST00000503591.2:c.393C>A
ENST00000508793.6:c.393C>A
ENST00000509690.6:c.-4C>A
ENST00000514944.6:c.114C>A
ENST00000604348.6:c.376-4C>A
ENST00000269305.9:c.393C>A
ENST00000269305.8:c.393C>A
ENST00000359597.8:c.393C>A
ENST00000413465.6:c.393C>A
ENST00000420246.6:c.393C>A
ENST00000445888.6:c.393C>A
ENST00000455263.6:c.393C>A
ENST00000504290.5:c.-4C>A
ENST00000504937.5:c.-4C>A
ENST00000505014.5:n.649C>A
ENST00000508793.5:c.393C>A
ENST00000509690.5:c.-4C>A
ENST00000510385.5:c.-4C>A
ENST00000514944.5:c.114C>A
ENST00000604348.5:c.376-4C>A
ENST00000610292.4:c.276C>A
ENST00000610538.4:c.276C>A
ENST00000610623.4:c.-85C>A
ENST00000615910.4:c.360C>A
ENST00000617185.4:c.393C>A
ENST00000618944.4:c.-85C>A
ENST00000619186.4:c.-85C>A
ENST00000619485.4:c.276C>A
ENST00000620739.4:c.276C>A
ENST00000622645.4:c.276C>A
ENST00000635293.1:c.276C>A
NM_001126112.2:c.393C>A
NM_001126113.2:c.393C>A
NM_001126114.2:c.393C>A
NM_001126115.1:c.-4C>A
NM_001126116.1:c.-4C>A
NM_001126117.1:c.-4C>A
NM_001126118.1:c.276C>A
NM_001276695.1:c.276C>A
NM_001276696.1:c.276C>A
NM_001276697.1:c.-85C>A
NM_001276698.1:c.-85C>A
NM_001276699.1:c.-85C>A
NM_001276760.1:c.276C>A
NM_001276761.1:c.276C>A
NM_001276695.2:c.276C>A
NM_001276696.2:c.276C>A
NM_001276697.2:c.-85C>A
NM_001276698.2:c.-85C>A
NM_001276699.2:c.-85C>A
NM_001276760.2:c.276C>A
NM_001276761.2:c.276C>A
NM_000546.6:c.393C>A
NM_001126112.3:c.393C>A
NM_001126113.3:c.393C>A
NM_001126114.3:c.393C>A
NM_001126115.2:c.-4C>A
NM_001126116.2:c.-4C>A
NM_001126117.2:c.-4C>A
NM_001126118.2:c.276C>A
NM_001276695.3:c.276C>A
NM_001276696.3:c.276C>A
NM_001276697.3:c.-85C>A
NM_001276698.3:c.-85C>A
NM_001276699.3:c.-85C>A
NM_001276760.3:c.276C>A
NM_001276761.3:c.276C>A
More

Uncertain Significance

Met criteria codes 4
PM2_Supporting BS3_Supporting BS2_Supporting PS4_Moderate
Not Met criteria codes 14
PS2 PS3 PS1 PP4 PP1 PP3 PVS1 PM1 PM5 BA1 BS4 BS1 BP4 BP7

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 2.2.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.393C>A variant in TP53 is a missense variant predicted to cause substitution of asparagine by lysine at amino acid 131 (p.Asn131Lys). This variant has been reported in 3 unrelated families] meeting Revised Chompret criteria with one of these cases including an individual under the age of 40 diagnosed with a HER2+ breast cancer. 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). 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 contributors). This variant has an allele frequency of 0.000008055 (13/1613958 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 partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). 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: PS4_Moderate, BS2_Supporting, PM2_Supporting, BS3_Supporting. (Bayesian Points: 1; VCEP specifications version 2.2; 2/6/2025)
Met criteria codes
PM2_Supporting
This variant has an allele frequency of 0.000008055 (13/1613958 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).
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).
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 contributors).
PS4_Moderate
This variant has been reported in 3 unrelated families meeting Revised Chompret criteria with one of these cases including an individual under the age of 40 diagnosed with a HER2+ breast cancer. 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).
Not Met criteria codes
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
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
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, SpliceAI predicts that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met).
PVS1
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
3 different missense variants (c.392A>T, p.Asn131Ile; c.392A>G, p.Asn131Ser; c.391A>T, p.Asn131Tyr) in the same codon have been reported (ClinVar Variation ID 428902, 1057941, 141988). However, this variant does not meet criteria for PM5 code application (PM5 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
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, SpliceAI predicts that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met).
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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