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_000546.5(TP53):c.396G>C (p.Lys132Asn)

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)
More

Likely Pathogenic

Met criteria codes 4
PM1 PM2_Supporting PP3_Moderate PS3
Not Met criteria codes 13
PP1 PM6 PM5 BA1 BS4 BS3 BS1 BS2 BP2 BP4 PS2 PS4 PS1

Evidence Links 4

Expert Panel

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.
Met criteria codes
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.
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
Not Met criteria codes
PP1
No known segregation information.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
BS2
Not seen in FLOSSIES database or in individuals age 60+ in the literature.
BP2
No reported incidences.
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.