Variant: NM_000546.6(TP53):c.329G>A (p.Arg110His)

CA000123

127808 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 00b45dfa-19f3-45de-975a-7b43bbc2be44

Approved on: 2025-01-16

Published on: 2025-01-16

HGVS expressions

NM_000546.6:c.329G>A
NM_000546.6(TP53):c.329G>A (p.Arg110His)
NC_000017.11:g.7676040C>T
CM000679.2:g.7676040C>T
NC_000017.10:g.7579358C>T
CM000679.1:g.7579358C>T
NC_000017.9:g.7520083C>T
NG_017013.2:g.16511G>A
ENST00000503591.2:c.329G>A
ENST00000508793.6:c.329G>A
ENST00000509690.6:c.-21-804G>A
ENST00000514944.6:c.96+342G>A
ENST00000604348.6:c.329G>A
ENST00000269305.9:c.329G>A
ENST00000269305.8:c.329G>A
ENST00000359597.8:c.329G>A
ENST00000413465.6:c.329G>A
ENST00000420246.6:c.329G>A
ENST00000445888.6:c.329G>A
ENST00000455263.6:c.329G>A
ENST00000503591.1:c.329G>A
ENST00000505014.5:n.585G>A
ENST00000508793.5:c.329G>A
ENST00000509690.5:c.-21-804G>A
ENST00000514944.5:c.96+342G>A
ENST00000604348.5:c.329G>A
ENST00000610292.4:c.212G>A
ENST00000610538.4:c.212G>A
ENST00000615910.4:c.329G>A
ENST00000617185.4:c.329G>A
ENST00000619485.4:c.212G>A
ENST00000620739.4:c.212G>A
ENST00000622645.4:c.212G>A
ENST00000635293.1:c.212G>A
NM_000546.5:c.329G>A
NM_001126112.2:c.329G>A
NM_001126113.2:c.329G>A
NM_001126114.2:c.329G>A
NM_001126118.1:c.212G>A
NM_001276695.1:c.212G>A
NM_001276696.1:c.212G>A
NM_001276760.1:c.212G>A
NM_001276761.1:c.212G>A
NM_001276695.2:c.212G>A
NM_001276696.2:c.212G>A
NM_001276760.2:c.212G>A
NM_001276761.2:c.212G>A
NM_001126112.3:c.329G>A
NM_001126113.3:c.329G>A
NM_001126114.3:c.329G>A
NM_001126118.2:c.212G>A
NM_001276695.3:c.212G>A
NM_001276696.3:c.212G>A
NM_001276760.3:c.212G>A
NM_001276761.3:c.212G>A

Likely Benign

• Met criteria codes: BS2 BS3_Supporting BP4

• Not Met criteria codes: BS4 BS1 BP2 BP5 BA1 PM1 PM5 PM2 PS2 PS4 PS3 PS1 PP1 PP3

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.2.0

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6: c.329G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 110 (p.Arg110His). 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 contributors). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00007119 (84/1,180,010 alleles) in the European (non-Finnish) population (PM2, BS1, and BA1 are not met). 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 = 0.0728; Align GVGD Class 0) are below the recommended thresholds (BayesDel < 0.16 and > -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). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BS3_Supporting, BP4. (Bayesian Points: -4; VCEP specifications version 2.1; 1/16/2025).

Met criteria codes

• BS2: 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 contributors).
• 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).
• BP4: Computational predictor scores (BayesDel = 0.0728; Align GVGD Class 0) are below the recommended thresholds (BayesDel < 0.16 and > -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).

Not Met criteria codes

• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: The highest population minor allele frequency in gnomAD v4.1.0 is 0.00007119 (84/1,180,010 alleles) in the European (non-Finnish) population (PM2, BS1, and BA1 are not met).
• BP2: These evidence codes are not currently applicable for TP53 VCEP curations
• BP5: These evidence codes are not currently applicable for TP53 VCEP curations
• BA1: The highest population minor allele frequency in gnomAD v4.1.0 is 0.00007119 (84/1,180,010 alleles) in the European (non-Finnish) population (PM2, BS1, and BA1 are not met).
• 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: 5 different missense variants (c.329_330delinsCC (p.Arg110Pro); c.329G>C (p.Arg110Pro); c.329G>T (p.Arg110Leu); c.328C>G (p.Arg110Gly); c.328C>T (p.Arg110Cys)) in the same codon have been reported (ClinVar Variation IDs: 641505; 233627; 406597; 823452; 142206). However, these variants all have more damaging Grantham scores than the variant under consideration (PM5 not met). Grantham: R>H = 29 R>P = 103 R>L = 102 R>G = 125 R>C = 180 R>S = 110
• PM2: The highest population minor allele frequency in gnomAD v4.1.0 is 0.00007119 (84/1,180,010 alleles) in the European (non-Finnish) population (PM2, BS1, and BA1 are not met).
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: This variant has been reported in 1 proband meeting Revised Chompret criteria and in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1 total point, meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. However, PS4 cannot be applied if PM2_Supporting is not met (PS4_not met; PMIDs: 23580068, Internal lab contributors).
• 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
• 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