The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

Variant: NM_000546.5(TP53):c.467G>A (p.Arg156His)

CA000216

127811 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome 1
Inheritance Mode: Autosomal dominant inheritance
UUID: ce57ae2b-139d-4e58-9f34-2bc237a4b09b
Approved on: 2021-02-22
Published on: 2021-10-11

HGVS expressions

NM_000546.5:c.467G>A
NM_000546.5(TP53):c.467G>A (p.Arg156His)
NC_000017.11:g.7675145C>T
CM000679.2:g.7675145C>T
NC_000017.10:g.7578463C>T
CM000679.1:g.7578463C>T
NC_000017.9:g.7519188C>T
NG_017013.2:g.17406G>A
ENST00000269305.9:c.467G>A
ENST00000269305.8:c.467G>A
ENST00000359597.8:n.467G>A
ENST00000413465.6:n.467G>A
ENST00000420246.6:c.467G>A
ENST00000445888.6:c.467G>A
ENST00000455263.6:c.467G>A
ENST00000504290.5:c.71G>A
ENST00000504937.5:c.71G>A
ENST00000505014.5:n.723G>A
ENST00000508793.5:c.467G>A
ENST00000509690.5:c.71G>A
ENST00000510385.5:c.71G>A
ENST00000514944.5:c.188G>A
ENST00000610292.4:c.350G>A
ENST00000610538.4:c.350G>A
ENST00000610623.4:c.-11G>A
ENST00000615910.4:n.434G>A
ENST00000617185.4:c.467G>A
ENST00000618944.4:c.-11G>A
ENST00000619186.4:c.-11G>A
ENST00000619485.4:c.350G>A
ENST00000620739.4:c.350G>A
ENST00000622645.4:c.350G>A
ENST00000635293.1:c.350G>A
NM_001126112.2:c.467G>A
NM_001126113.2:c.467G>A
NM_001126114.2:c.467G>A
NM_001126115.1:c.71G>A
NM_001126116.1:c.71G>A
NM_001126117.1:c.71G>A
NM_001126118.1:c.350G>A
NM_001276695.1:c.350G>A
NM_001276696.1:c.350G>A
NM_001276697.1:c.-11G>A
NM_001276698.1:c.-11G>A
NM_001276699.1:c.-11G>A
NM_001276760.1:c.350G>A
NM_001276761.1:c.350G>A
NM_001276695.2:c.350G>A
NM_001276696.2:c.350G>A
NM_001276697.2:c.-11G>A
NM_001276698.2:c.-11G>A
NM_001276699.2:c.-11G>A
NM_001276760.2:c.350G>A
NM_001276761.2:c.350G>A
NM_000546.6:c.467G>A
NM_001126112.3:c.467G>A
NM_001126113.3:c.467G>A
NM_001126114.3:c.467G>A
NM_001126115.2:c.71G>A
NM_001126116.2:c.71G>A
NM_001126117.2:c.71G>A
NM_001126118.2:c.350G>A
NM_001276695.3:c.350G>A
NM_001276696.3:c.350G>A
NM_001276697.3:c.-11G>A
NM_001276698.3:c.-11G>A
NM_001276699.3:c.-11G>A
NM_001276760.3:c.350G>A
NM_001276761.3:c.350G>A
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Uncertain Significance

Met criteria codes 3
BS2_Supporting PS4_Moderate BS3_Supporting
Not Met criteria codes 14
PS2 PS1 PS3 PP1 PP3 PM1 PM5 PM6 PM2 BA1 BS4 BS1 BP2 BP4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
This variant has been reported in 4 probands meeting Revised Chompret criteria (PS4_Supporting; Internal laboratory and clinical contributors, SCV000186315.7). This variant has been observed in 4 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor, SCV000186315.7). Transactivation assays show a 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). In summary, the clinical significance of TP53 c.467G>A (p.Arg156His) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PS4_moderate; BS2_supporting; BS4_supporting.
Met criteria codes
BS2_Supporting
R156H is observed 1x in the FLOSSIES database, 4 cancer free 60+ from Ambry laboratories. 9 "potential" cancer free 60+ from Invitae, but could not be confirmed.
PS4_Moderate
Proband counting: Total = 2pts. Chompret to count as 0.5 and 1 for LFS. PMID:30709875 (not counted, fails to meet Chompret because cancers of relatives are unknown. Subject has pleomorphic sarcoma and treatment-AML, sister died 3yr unknown cancer, father died 42yr unknown cancer). PMID: 10435620. Not counted due to two variants. Subject and maternal lineage with two variants on one allele (R267Q and R156H) are LFS. PMID:28477317: not counted. Subject has fibrolamellar hepatocellular carcinoma at 14yr and a first cousin with osteosarcoma at age 10. PMID: 30092803: not counted, male with ileocecal valve adenocarcinoma at age 36 no family history available.; IARC family Ee100 (unpublished, in IARC): not counted. Female with breast cancer age 38 and first degree relative with sarcoma age 57. IARC family HEY10 PMID: 21059199 not counted 32 yr old with invasive ductal carcinoma. Authors note a family history of Li-Fraumeni Syndrome but it is not further detailed. Ambry laboratory had two cases that met Revised Chompret = 1 point. Internal clinical contributor had 2 cases that met Revised Chompret = 1 point.
BS3_Supporting
Arg156His is partially functional in Kato data (52.65%). Giacomelli et al data shows p53WTNutlin3 Z-score is 0.85 (with cut off for dominant negative activity >=0.61) but the etoposide LOF Z-score is 0.178 (with <= -0.21as the cut off for loss of function). Kotler et al data is -2.72 (no LOF). Combined, this constitutes a BS3_Supporting evidence code.
Not Met criteria codes
PS2
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
PS3
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
Variant is Class C0 in align-GVGD (>C15 is considered pathogenic) and 0.1907 in BayesDel (>=0.16 is considered pathogenic). As these are not in concordance, the code cannot be applied.
PM1
It is not a known hotspot and has no entry in the somatic hotspot database (cancerhotspots.org)
PM5
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
10/28/19 variant is 0.00002 (4/251268) in Gnomad. All 4 alleles are in European (non-Finnish). It fails to meet the BS1 criteria of >0.0003 but <0.001 minor allele frequency, and does not have a minimum of 5 alleles in any one population.
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
10/28/19 variant is 0.00002 (4/251268) in Gnomad. All 4 alleles are in European (non-Finnish). It fails to meet the BS1 criteria of >0.0003 but <0.001 minor allele frequency, and does not have a minimum of 5 alleles in any one population.
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
Variant is Class C0 in align-GVGD (>C15 is considered pathogenic) and 0.1907 in BayesDel (>=0.16 is considered pathogenic). As these are not in concordance, the code cannot be applied.
Curation History
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