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]

Variant: NM_000546.5(TP53):c.396G>C (p.Lys132Asn)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA16603044

376624 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: d817c4c8-1df0-4998-acec-3488a11fc4b0

Approved on: 2022-03-18

Published on: 2022-03-18

HGVS expressions

NM_000546.5:c.396G>C

NM_000546.5(TP53):c.396G>C (p.Lys132Asn)

NC_000017.11:g.7675216C>G

CM000679.2:g.7675216C>G

NC_000017.10:g.7578534C>G

CM000679.1:g.7578534C>G

NC_000017.9:g.7519259C>G

NG_017013.2:g.17335G>C

ENST00000269305.9:c.396G>C

ENST00000269305.8:c.396G>C

ENST00000359597.8:n.396G>C

ENST00000413465.6:n.396G>C

ENST00000420246.6:c.396G>C

ENST00000445888.6:c.396G>C

ENST00000455263.6:c.396G>C

ENST00000504290.5:c.-1G>C

ENST00000504937.5:c.-1G>C

ENST00000505014.5:n.652G>C

ENST00000508793.5:c.396G>C

ENST00000509690.5:c.-1G>C

ENST00000510385.5:c.-1G>C

ENST00000514944.5:c.117G>C

ENST00000604348.5:c.376-1G>C

ENST00000610292.4:c.279G>C

ENST00000610538.4:c.279G>C

ENST00000610623.4:c.-82G>C

ENST00000615910.4:n.363G>C

ENST00000617185.4:c.396G>C

ENST00000618944.4:c.-82G>C

ENST00000619186.4:c.-82G>C

ENST00000619485.4:c.279G>C

ENST00000620739.4:c.279G>C

ENST00000622645.4:c.279G>C

ENST00000635293.1:c.279G>C

NM_001126112.2:c.396G>C

NM_001126113.2:c.396G>C

NM_001126114.2:c.396G>C

NM_001126115.1:c.-1G>C

NM_001126116.1:c.-1G>C

NM_001126117.1:c.-1G>C

NM_001126118.1:c.279G>C

NM_001276695.1:c.279G>C

NM_001276696.1:c.279G>C

NM_001276697.1:c.-82G>C

NM_001276698.1:c.-82G>C

NM_001276699.1:c.-82G>C

NM_001276760.1:c.279G>C

NM_001276761.1:c.279G>C

NM_001276695.2:c.279G>C

NM_001276696.2:c.279G>C

NM_001276697.2:c.-82G>C

NM_001276698.2:c.-82G>C

NM_001276699.2:c.-82G>C

NM_001276760.2:c.279G>C

NM_001276761.2:c.279G>C

NM_000546.6:c.396G>C

NM_001126112.3:c.396G>C

NM_001126113.3:c.396G>C

NM_001126114.3:c.396G>C

NM_001126115.2:c.-1G>C

NM_001126116.2:c.-1G>C

NM_001126117.2:c.-1G>C

NM_001126118.2:c.279G>C

NM_001276695.3:c.279G>C

NM_001276696.3:c.279G>C

NM_001276697.3:c.-82G>C

NM_001276698.3:c.-82G>C

NM_001276699.3:c.-82G>C

NM_001276760.3:c.279G>C

NM_001276761.3:c.279G>C

NM_000546.6(TP53):c.396G>C (p.Lys132Asn)

Likely Pathogenic

PS3 PM1 PM2_Supporting PP3_Moderate

PS2 PS4 PS1 BP2 BP4 BA1 PP1 PM5 PM6 BS2 BS4 BS3 BS1

Evidence Links 4

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

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 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)). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, TP53 c.396G>C (p.Lys132Asn) meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PS3, PP3_Moderate, PM1, PM2_Supporting.

PS3

Experimental studies show this variant to be non-functional (Kato 2003) and to demonstrate both dominant negative effect (DNE) and loss of function (LOF) (Dearth 2007, Giacomelli 2018 and Kotler 2018).

Evidence for LOF PubMed:29979965

Shows DNE and LOF PubMed:30224644

Shows variant to be non-functional. PubMed:12826609

Evidence of LOF and DNE PubMed:16861262

PM1

Not in hot spot codon but seen in 30 tumor samples on cancerhotspots.org.

PM2_Supporting

Absent from population databases.

PP3_Moderate

aGVGD class C65 and BayesDel >0.16. Strength modified as described by VCEP.

PS2

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

PS4

No published case reports of germline variant in the literature. Identified at least once in an unpublished case of a young female with rhabdomyosarcoma (parents not tested) not meeting classic LFS or Chompret criteria.

PS1

c.396G>T (p.Lys132Asn) has also been seen (ClinVar ID: 634773) but has not been evaluated by TP53 VCEP and is currently designated a VUS by Invitae

BP2

No reported incidences.

BP4

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

PP1

No known segregation information.

PM5

NM_000546.5(TP53):c.395A>T (p.Lys132Met) ClinVar ID: 376629 (Not evaluated by VCEP; VUS by Invitae) NM_000546.5(TP53):c.395A>C (p.Lys132Thr) ClinVar ID: 376627 (Not evaluated by VCEP; LP by somatic entries only) NM_000546.5(TP53):c.395A>G (p.Lys132Arg) ClinVar ID: 376625 (Not evaluated by VCEP; VUS by Invitae) NM_000546.5(TP53):c.394A>C (p.Lys132Gln) ClinVar ID: 376628 (Not evaluated by VCEP; LP by somatic entries only) NM_000546.5(TP53):c.394A>G (p.Lys132Glu) ClinVar ID; 376626 (Not evaluated by VCEP; conflicting VUS (Invitae)/ LP (Ambry) interpretations

PM6

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

BS2

Not seen in FLOSSIES database or in individuals age 60+ in the literature.

BS4

No known segregation information.

BS3

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

BS1

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

Curation History

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