Evidence Repository - Clinical Genome Resources

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

Link to SEPIO compliant JSON-LD document

Variant: NM_001126112.2(TP53):c.711G>A (p.Met237Ile)

CA000349

142714 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome 1

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 98acfed4-de66-4a8c-b6ba-bc9a67cd4189

Approved on: 2021-04-20

Published on: 2021-06-16

HGVS expressions

NM_001126112.2:c.711G>A

NM_001126112.2(TP53):c.711G>A (p.Met237Ile)

ENST00000269305.9:c.711G>A

ENST00000269305.8:c.711G>A

ENST00000359597.8:n.711G>A

ENST00000413465.6:n.711G>A

ENST00000420246.6:c.711G>A

ENST00000445888.6:c.711G>A

ENST00000455263.6:c.711G>A

ENST00000504290.5:c.315G>A

ENST00000504937.5:c.315G>A

ENST00000509690.5:c.315G>A

ENST00000510385.5:c.315G>A

ENST00000514944.5:c.432G>A

ENST00000610292.4:c.594G>A

ENST00000610538.4:c.594G>A

ENST00000610623.4:c.234G>A

ENST00000615910.4:n.678G>A

ENST00000617185.4:c.711G>A

ENST00000618944.4:c.234G>A

ENST00000619186.4:c.234G>A

ENST00000619485.4:c.594G>A

ENST00000620739.4:c.594G>A

ENST00000622645.4:c.594G>A

ENST00000635293.1:c.594G>A

NM_000546.5:c.711G>A

NM_001126113.2:c.711G>A

NM_001126114.2:c.711G>A

NM_001126115.1:c.315G>A

NM_001126116.1:c.315G>A

NM_001126117.1:c.315G>A

NM_001126118.1:c.594G>A

NM_001276695.1:c.594G>A

NM_001276696.1:c.594G>A

NM_001276697.1:c.234G>A

NM_001276698.1:c.234G>A

NM_001276699.1:c.234G>A

NM_001276760.1:c.594G>A

NM_001276761.1:c.594G>A

NM_001276695.2:c.594G>A

NM_001276696.2:c.594G>A

NM_001276697.2:c.234G>A

NM_001276698.2:c.234G>A

NM_001276699.2:c.234G>A

NM_001276760.2:c.594G>A

NM_001276761.2:c.594G>A

NM_000546.6:c.711G>A

NM_001126112.3:c.711G>A

NM_001126113.3:c.711G>A

NM_001126114.3:c.711G>A

NM_001126115.2:c.315G>A

NM_001126116.2:c.315G>A

NM_001126117.2:c.315G>A

NM_001126118.2:c.594G>A

NM_001276695.3:c.594G>A

NM_001276696.3:c.594G>A

NM_001276697.3:c.234G>A

NM_001276698.3:c.234G>A

NM_001276699.3:c.234G>A

NM_001276760.3:c.594G>A

NM_001276761.3:c.594G>A

NC_000017.11:g.7674252C>T

CM000679.2:g.7674252C>T

NC_000017.10:g.7577570C>T

CM000679.1:g.7577570C>T

NC_000017.9:g.7518295C>T

NG_017013.2:g.18299G>A

Pathogenic

PM1 PP1_Moderate PS4 PS3 PM6_Supporting

BA1 BP4 BS2 BS3 BS1 PP3 PM2 PM5

Evidence Links 0

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

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 evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in 1 proband meeting Classic LFS criteria and 4 probands meeting Chompret criteria (PS4; PMID: 11370630, 25945745, NIH, Invitae, Ambry). This variant was found to co-segregate with disease in multiple affected family members, with 5 or 6 meioses observed (PP1_Moderate; NIH, Invitae). There is one de novo observation in a proband with breast and thyroid cancer in her 30s without parental confirmation (PM6_Supporting; GeneDx). In summary, TP53 c.711G>A (p.Met237Ile) meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM1, PS3, PS4, PP1_Moderate, PM6_Supporting.

PM1

55/64 samples on cancerhotspots.com

PP1_Moderate

6 meioses in across 2 families (NIH, Invitae)

PS4

NIH: 1 Chompret; 1 classic = 1.5 pts Literature: Chompret = 0.5 pts (PMID:11370630) and Classical = 1 point (PMID: 25945745) Ambry labs: Chompret = 0.5 pts Invitae Lab: Chompret = 0.5 pts 4 total points

PS3

Nonfunctional by Kato; LOF by Kotler; LOF+DNE by Giacomelli

PM6_Supporting

Assumed de novo in female with breast cancer in 30s (0.5 pts; GeneDx)

BA1

Present in 1/17692 East Asian alleles in gnomAD (non-cancer); AF = 0.0057%

BP4

aGVGD class C0 (benign) but BayesDel 0.4419>0.16 (path)

BS2

Absent from FLOSSIES. Internal data not received by some ClinVar submitters.

BS3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

Present in 1/17692 East Asian alleles in gnomAD (non-cancer); AF = 0.0057%

PP3

aGVGD class C0 (benign) but BayesDel 0.4419>0.16 (path)

PM2

Present in 1/17692 East Asian alleles in gnomAD (non-cancer); AF = 0.0057%

PM5

M237T (ID: 481069, VUSx2); M327R (ID: 419524, VUSx1); M237K (ID: 376636, LP somatic only); M237V (ID: 182934, VUSx2)

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