Variant: NM_000546.5(TP53):c.704A>G (p.Asn235Ser)

CA000343

127821 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 38d9dfad-aa7b-409a-9fd8-3f6898fb8c57

Approved on: 2024-08-05

Published on: 2024-08-05

HGVS expressions

NM_000546.5:c.704A>G
NM_000546.5(TP53):c.704A>G (p.Asn235Ser)
NC_000017.11:g.7674259T>C
CM000679.2:g.7674259T>C
NC_000017.10:g.7577577T>C
CM000679.1:g.7577577T>C
NC_000017.9:g.7518302T>C
NG_017013.2:g.18292A>G
ENST00000503591.2:c.704A>G
ENST00000508793.6:c.704A>G
ENST00000509690.6:c.308A>G
ENST00000514944.6:c.425A>G
ENST00000604348.6:c.683A>G
ENST00000269305.9:c.704A>G
ENST00000269305.8:c.704A>G
ENST00000359597.8:c.704A>G
ENST00000413465.6:c.704A>G
ENST00000420246.6:c.704A>G
ENST00000445888.6:c.704A>G
ENST00000455263.6:c.704A>G
ENST00000504290.5:c.308A>G
ENST00000504937.5:c.308A>G
ENST00000509690.5:c.308A>G
ENST00000510385.5:c.308A>G
ENST00000514944.5:c.425A>G
ENST00000574684.1:n.99A>G
ENST00000610292.4:c.587A>G
ENST00000610538.4:c.587A>G
ENST00000610623.4:c.227A>G
ENST00000615910.4:c.671A>G
ENST00000617185.4:c.704A>G
ENST00000618944.4:c.227A>G
ENST00000619186.4:c.227A>G
ENST00000619485.4:c.587A>G
ENST00000620739.4:c.587A>G
ENST00000622645.4:c.587A>G
ENST00000635293.1:c.587A>G
NM_001126112.2:c.704A>G
NM_001126113.2:c.704A>G
NM_001126114.2:c.704A>G
NM_001126115.1:c.308A>G
NM_001126116.1:c.308A>G
NM_001126117.1:c.308A>G
NM_001126118.1:c.587A>G
NM_001276695.1:c.587A>G
NM_001276696.1:c.587A>G
NM_001276697.1:c.227A>G
NM_001276698.1:c.227A>G
NM_001276699.1:c.227A>G
NM_001276760.1:c.587A>G
NM_001276761.1:c.587A>G
NM_001276695.2:c.587A>G
NM_001276696.2:c.587A>G
NM_001276697.2:c.227A>G
NM_001276698.2:c.227A>G
NM_001276699.2:c.227A>G
NM_001276760.2:c.587A>G
NM_001276761.2:c.587A>G
NM_000546.6:c.704A>G
NM_001126112.3:c.704A>G
NM_001126113.3:c.704A>G
NM_001126114.3:c.704A>G
NM_001126115.2:c.308A>G
NM_001126116.2:c.308A>G
NM_001126117.2:c.308A>G
NM_001126118.2:c.587A>G
NM_001276695.3:c.587A>G
NM_001276696.3:c.587A>G
NM_001276697.3:c.227A>G
NM_001276698.3:c.227A>G
NM_001276699.3:c.227A>G
NM_001276760.3:c.587A>G
NM_001276761.3:c.587A>G

Benign

• Met criteria codes: BS4 BS3 BS2 BP4

• Not Met criteria codes: BS1 PS1 PS2 PS4 PS3 BA1 PP4 PP1 PP3 PM6 PM2 PM5 PM1

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.0.0

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6: c.704A>G variant in TP53 is a missense variant predicted to cause substitution of asparagine by serine at amino acid 235 (p.Asn235Ser). 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: SCV000185528.8). 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). This variant has been reported not to segregate with Li-Fraumeni syndrome in four affected family members from one family (BS4; PMID 17318340). Computational predictor scores (BayesDel = -0.0342; 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_Moderate). 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, BS3, BS4, BP4_Moderate. (Bayesian Points: -14; VCEP specifications version 2.0; 7/24/2024)

Met criteria codes

• BS4: This variant has been reported not to segregate with Li-Fraumeni syndrome in four affected family members from one family (BS4; PMID 17318340).
• 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 (PMIDs: 12826609, 29979965, 30224644) (BS3)
• 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: SCV000185528.8).
• BP4: BP4_MODERATE MET Computational predictor scores (BayesDel = -0.0342; 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_Moderate).

Not Met criteria codes

• BS1: 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
• BA1: 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
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: The highest population minor allele frequency in gnomAD v41.0 is 0.0002890 (341/1179786 alleles) in the European (non-Finnish) population (PM2, BS1, and BA1 are not met).
• PM5: Another missense variant with equal or lesser impact (c.703A>T, p.Asn235Tyr) in the same codon has been reported (ClinVar Variation ID 188206). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PM5 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).