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]
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Variant: NM_000546.5(TP53):c.523C>T (p.Arg175Cys)

CA002442

245851 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 3699ed0e-e5f6-4457-bee4-961ef507dd2c
Approved on: 2022-06-27
Published on: 2022-06-27

HGVS expressions

NM_000546.5:c.523C>T
NM_000546.5(TP53):c.523C>T (p.Arg175Cys)
NC_000017.11:g.7675089G>A
CM000679.2:g.7675089G>A
NC_000017.10:g.7578407G>A
CM000679.1:g.7578407G>A
NC_000017.9:g.7519132G>A
NG_017013.2:g.17462C>T
ENST00000269305.9:c.523C>T
ENST00000269305.8:c.523C>T
ENST00000359597.8:n.523C>T
ENST00000413465.6:n.523C>T
ENST00000420246.6:c.523C>T
ENST00000445888.6:c.523C>T
ENST00000455263.6:c.523C>T
ENST00000504290.5:c.127C>T
ENST00000504937.5:c.127C>T
ENST00000505014.5:n.779C>T
ENST00000509690.5:c.127C>T
ENST00000510385.5:c.127C>T
ENST00000514944.5:c.244C>T
ENST00000574684.1:n.31C>T
ENST00000610292.4:c.406C>T
ENST00000610538.4:c.406C>T
ENST00000610623.4:c.46C>T
ENST00000615910.4:n.490C>T
ENST00000617185.4:c.523C>T
ENST00000618944.4:c.46C>T
ENST00000619186.4:c.46C>T
ENST00000619485.4:c.406C>T
ENST00000620739.4:c.406C>T
ENST00000622645.4:c.406C>T
ENST00000635293.1:c.406C>T
NM_001126112.2:c.523C>T
NM_001126113.2:c.523C>T
NM_001126114.2:c.523C>T
NM_001126115.1:c.127C>T
NM_001126116.1:c.127C>T
NM_001126117.1:c.127C>T
NM_001126118.1:c.406C>T
NM_001276695.1:c.406C>T
NM_001276696.1:c.406C>T
NM_001276697.1:c.46C>T
NM_001276698.1:c.46C>T
NM_001276699.1:c.46C>T
NM_001276760.1:c.406C>T
NM_001276761.1:c.406C>T
NM_001276695.2:c.406C>T
NM_001276696.2:c.406C>T
NM_001276697.2:c.46C>T
NM_001276698.2:c.46C>T
NM_001276699.2:c.46C>T
NM_001276760.2:c.406C>T
NM_001276761.2:c.406C>T
NM_000546.6:c.523C>T
NM_001126112.3:c.523C>T
NM_001126113.3:c.523C>T
NM_001126114.3:c.523C>T
NM_001126115.2:c.127C>T
NM_001126116.2:c.127C>T
NM_001126117.2:c.127C>T
NM_001126118.2:c.406C>T
NM_001276695.3:c.406C>T
NM_001276696.3:c.406C>T
NM_001276697.3:c.46C>T
NM_001276698.3:c.46C>T
NM_001276699.3:c.46C>T
NM_001276760.3:c.406C>T
NM_001276761.3:c.406C>T
NM_000546.6(TP53):c.523C>T (p.Arg175Cys)
More

Uncertain Significance

Met criteria codes 5
PP3_Moderate PS4_Supporting BS3_Supporting PM1 BS2_Supporting
Not Met criteria codes 14
BS4 BS1 BP7 BP2 BP4 PS2 PS3 PS1 PP1 BA1 PM6 PM2 PM5 PVS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). This variant is within a codon that is an established hotspot in the TP53 gene (PM1). This variant has been reported in 2 probands meeting Revised Chompret criteria (PS4_Supporting; PMID: 31119730, internal laboratory contributor(SCV000903055.2)). Transactivation assays show partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644). This variant has been observed in 5 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor, SCV000833097.4). In summary, the clinical significance of TP53 c.523C>T (p.Arg175Cys) is uncertain for Li-Fraumeni Syndrome. ACMG/AMP criteria applied, as specified by the TP53 Expert Panel: PP3_Moderate; PM1; PS4_Supporting; BS3_Supporting; BS2_Supporting.
Met criteria codes
PP3_Moderate
Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Align-GVGD = Class C65 BayesDel = 0.544256 (score > 0.16, as requested)
PS4_Supporting
Two cases in TCGA: - TCGA-BH-A18l: breast cancer (53) - 0 point - TCGA-06-2563: glioblastoma (72) - 0 point IARC: There are four entries of confirmed germline p.R175C carriers in the IARC database v.R20. - ZA08385-1 (Same entry as PUBMED ID 28724667) - SAR19-15-II-1: squamous cell carcinoma, at the age of 65 years old - 0 point - SAR19-15-IV-1: neuroectodermal tumor, at the age of 9 years old - 0 point - WEB18-3: ovary cancer, at 45 years old. - 0 point Clinvar data: One women affected with breast cancer at late 20s years old. Affecting one breast. Family history not reported. This patient therefore meets Chompret 2015 LFS criteria (early-onset breast cancer (<31yo) irrespective of family history = 0.5 points. (SCV000903055.2). PMID 31119730: Patient with breast cancer diagnosed at 30 years of age = 0.5 points
BS3_Supporting
Kato assay = partially functional (median = 72.5) Giacomelli = notDNE_notLOF Kotler = noLOF (score = -2.535)
PM1
Code is scored based on the its location within the hotspot codon 175. Cancer hotspots website describes 8 somatic occurrences (does not reach threshold of 10, as set by the ClinGen TP53 group)
BS2_Supporting
Variant not found in the FLOSSIES database. Variant found in woman with ovarian cancer at 64. Family history of breast, leukemia, and colon cancers on both sides. Does not meet any clinical criteria. Counts as woman unaffected at 60 (PMID: 22006311). Internal lab with 5 cases of women cancer free by age 60 (SCV000833097.4)
Not Met criteria codes
BS4
No enough evidence
BS1
Global allele frequency in gnomAD v2.1.1 non-cancer subset = 0.00001492 (4 alleles)
BP7
Variant is not synonymous
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
Not applied since variant meets PP3_moderate.
PS2
No enough evidence
PS3
Variant does not meet this criteria since BS3_Supporting has been scored.
PS1
There is no previous "pathogenic" p.R175C variant with a nucleotide change different than c.523C>T. According to the IARC database, the variant c.523C>T creates a new splice donor site (based on HSF_V2.3)
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
Global allele frequency in gnomAD v2.1.1 non-cancer subset = 0.00001492 (4 alleles)
PM6
No enough evidence
PM2
Global allele frequency in gnomAD v2.1.1 non-cancer subset = 0.00001492 (4 alleles)
PM5
PM5 not applied once this variant is located within a hotspot (PM1) Other variants in this codon: - Variant p.R175H: widely known as pathogenic - Variants p.R175G: pathogenic/likely pathogenic entries in ClinVar - Variant p.R175L: conflicting interpretations These other variants not yet assessed by VCEP.
PVS1
Variant is not a null variant
Curation History
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