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.319T>C (p.Tyr107His)

CA000104

140786 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: b172bcbe-5cff-4ba5-9ba2-482b4e1e357d
Approved on: 2024-08-05
Published on: 2024-08-05

HGVS expressions

NM_000546.5(TP53):c.319T>C
NM_000546.5(TP53):c.319T>C (p.Tyr107His)
NC_000017.11:g.7676050A>G
CM000679.2:g.7676050A>G
NC_000017.10:g.7579368A>G
CM000679.1:g.7579368A>G
NC_000017.9:g.7520093A>G
NG_017013.2:g.16501T>C
ENST00000503591.2:c.319T>C
ENST00000508793.6:c.319T>C
ENST00000509690.6:c.-21-814T>C
ENST00000514944.6:c.96+332T>C
ENST00000604348.6:c.319T>C
ENST00000269305.9:c.319T>C
ENST00000269305.8:c.319T>C
ENST00000359597.8:c.319T>C
ENST00000413465.6:c.319T>C
ENST00000420246.6:c.319T>C
ENST00000445888.6:c.319T>C
ENST00000455263.6:c.319T>C
ENST00000503591.1:c.319T>C
ENST00000505014.5:n.575T>C
ENST00000508793.5:c.319T>C
ENST00000509690.5:c.-21-814T>C
ENST00000514944.5:c.96+332T>C
ENST00000604348.5:c.319T>C
ENST00000610292.4:c.202T>C
ENST00000610538.4:c.202T>C
ENST00000615910.4:c.319T>C
ENST00000617185.4:c.319T>C
ENST00000619485.4:c.202T>C
ENST00000620739.4:c.202T>C
ENST00000622645.4:c.202T>C
ENST00000635293.1:c.202T>C
NM_000546.5:c.319T>C
NM_001126112.2:c.319T>C
NM_001126113.2:c.319T>C
NM_001126114.2:c.319T>C
NM_001126118.1:c.202T>C
NM_001276695.1:c.202T>C
NM_001276696.1:c.202T>C
NM_001276760.1:c.202T>C
NM_001276761.1:c.202T>C
NM_001276695.2:c.202T>C
NM_001276696.2:c.202T>C
NM_001276760.2:c.202T>C
NM_001276761.2:c.202T>C
NM_000546.6:c.319T>C
NM_001126112.3:c.319T>C
NM_001126113.3:c.319T>C
NM_001126114.3:c.319T>C
NM_001126118.2:c.202T>C
NM_001276695.3:c.202T>C
NM_001276696.3:c.202T>C
NM_001276760.3:c.202T>C
NM_001276761.3:c.202T>C
More

Benign

Met criteria codes 4
BS2 BS1 BP4 BS3_Supporting
Not Met criteria codes 12
BA1 BS4 PS1 PS2 PS4 PS3 PP4 PP1 PP3 PM2 PM5 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 2.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.319T>C variant in TP53 is a missense variant predicted to cause substitution of Tyrosine by Histidine at amino acid 107 (p.Tyr107His). This variant has been observed in at least 8 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; Internal lab contributor: ClinVar SCV: SCV000172807.10). The filtering allele frequency is 0.0007936 in the African/African American population in gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.0003 but <0.001) for BS1, and therefore meets this criterion (BS1). 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). Computational predictor scores (BayesDel = 0.0202 Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 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). 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: BS1, BS2, BS3_supporting, BP4 (Bayesian Points: -10; VCEP specifications version 2.0; 7/24/2024).
Met criteria codes
BS2
This variant has been observed in at least 8 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; Internal lab contributor: ClinVar SCV: SCV000172807.10).
BS1
The filtering allele frequency is 0.0007936 in the African/African American population in gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.0003 but <0.001) for BS1, and therefore meets this criterion (BS1).
BP4
Computational predictor scores (BayesDel = 0.0202 Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 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).
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).
Not Met criteria codes
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
PS1
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
PS4
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
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
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
4 different missense variants (c.320A>G; p.Tyr107Cys;c.320A>C; p.Tyr107Ser; c.319T>G; p.Tyr107Asp; c.319T>A; p.Tyr107Asn) in the same codon have been reported (ClinVar Variation ID 142691, 142414, 641482, 406572). 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).
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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