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]
  • See Evidence submitted by expert panel for details.

Variant: NM_001126112.2(TP53):c.380C>A (p.Ser127Tyr)

CA397843908

656751 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 69da5ddc-e144-48e0-aa76-30754f54757b
Approved on: 2021-04-20
Published on: 2021-06-16

HGVS expressions

NM_001126112.2:c.380C>A
NM_001126112.2(TP53):c.380C>A (p.Ser127Tyr)
NC_000017.11:g.7675232G>T
CM000679.2:g.7675232G>T
NC_000017.10:g.7578550G>T
CM000679.1:g.7578550G>T
NC_000017.9:g.7519275G>T
NG_017013.2:g.17319C>A
ENST00000269305.9:c.380C>A
ENST00000269305.8:c.380C>A
ENST00000359597.8:n.380C>A
ENST00000413465.6:n.380C>A
ENST00000420246.6:c.380C>A
ENST00000445888.6:c.380C>A
ENST00000455263.6:c.380C>A
ENST00000503591.1:c.380C>A
ENST00000504290.5:c.-17C>A
ENST00000504937.5:c.-17C>A
ENST00000505014.5:n.636C>A
ENST00000508793.5:c.380C>A
ENST00000509690.5:c.-17C>A
ENST00000510385.5:c.-17C>A
ENST00000514944.5:c.101C>A
ENST00000604348.5:c.376-17C>A
ENST00000610292.4:c.263C>A
ENST00000610538.4:c.263C>A
ENST00000610623.4:c.-98C>A
ENST00000615910.4:n.347C>A
ENST00000617185.4:c.380C>A
ENST00000618944.4:c.-98C>A
ENST00000619186.4:c.-98C>A
ENST00000619485.4:c.263C>A
ENST00000620739.4:c.263C>A
ENST00000622645.4:c.263C>A
ENST00000635293.1:c.263C>A
NM_000546.5:c.380C>A
NM_001126113.2:c.380C>A
NM_001126114.2:c.380C>A
NM_001126115.1:c.-17C>A
NM_001126116.1:c.-17C>A
NM_001126117.1:c.-17C>A
NM_001126118.1:c.263C>A
NM_001276695.1:c.263C>A
NM_001276696.1:c.263C>A
NM_001276697.1:c.-98C>A
NM_001276698.1:c.-98C>A
NM_001276699.1:c.-98C>A
NM_001276760.1:c.263C>A
NM_001276761.1:c.263C>A
NM_001276695.2:c.263C>A
NM_001276696.2:c.263C>A
NM_001276697.2:c.-98C>A
NM_001276698.2:c.-98C>A
NM_001276699.2:c.-98C>A
NM_001276760.2:c.263C>A
NM_001276761.2:c.263C>A
NM_000546.6:c.380C>A
NM_001126112.3:c.380C>A
NM_001126113.3:c.380C>A
NM_001126114.3:c.380C>A
NM_001126115.2:c.-17C>A
NM_001126116.2:c.-17C>A
NM_001126117.2:c.-17C>A
NM_001126118.2:c.263C>A
NM_001276695.3:c.263C>A
NM_001276696.3:c.263C>A
NM_001276697.3:c.-98C>A
NM_001276698.3:c.-98C>A
NM_001276699.3:c.-98C>A
NM_001276760.3:c.263C>A
NM_001276761.3:c.263C>A
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Pathogenic

Met criteria codes 6
PM2_Supporting PP1 PM1 PP3_Moderate PS3 PS4_Supporting
Not Met criteria codes 4
BS3 BS2 BP4 PS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Transactivation assays show a low functioning allele according to Kato, et al. and there is an in vitro proliferation assay demonstrating loss of function (PS3; PMID: 12826609, PMID: 25584008). This variant has been reported in 2 probands meeting Chompret criteria (PS4; internal laboratory contributors). This variant was found to co-segregate with disease in multiple affected family members, with 3 meioses observed (PP1; internal laboratory contributor). In summary, TP53 c.380C>A (p.Ser127Tyr) meets criteria to be classified as Pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3_Moderate, PM1, PS3, PS4_Supporting, PP1.
Met criteria codes
PM2_Supporting
Absent from gnomAD (non-cancer)
PP1
Variant observed in 3 meioses in family segregating breast and brain cancer in Ambry internal data
PM1
Yes, 10/48 samples on cancerhotspots.com
PP3_Moderate
aGVGD = C65; BayesDel = 0.6001
PS3
Kato non-functional, Kotler LOF, Giacomelli DNE but not LOF.
PS4_Supporting
1 Chompret case from NIH cohort = 0.5 pts. 1 Chompret case from Ambry labs = 0.5 points. 1 point total.
Not Met criteria codes
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
Not present in FLOSSIES. Internal lab data not received.
BP4
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
Curation History
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