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]
Link to SEPIO compliant JSON-LD document
  • See Evidence submitted by expert panel for details.

Variant: NM_000546.5(TP53):c.949C>A (p.Gln317Lys)

CA001204

231008 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d1ca3ef5-f2a9-4242-be3b-b59dff4af099

HGVS expressions

NM_000546.5:c.949C>A
NM_000546.5(TP53):c.949C>A (p.Gln317Lys)
ENST00000269305.9:c.949C>A
ENST00000269305.8:c.949C>A
ENST00000359597.8:n.949C>A
ENST00000413465.6:n.782+602C>A
ENST00000420246.6:c.949C>A
ENST00000445888.6:c.949C>A
ENST00000455263.6:c.949C>A
ENST00000504290.5:c.553C>A
ENST00000504937.5:c.553C>A
ENST00000509690.5:c.553C>A
ENST00000510385.5:c.553C>A
ENST00000576024.1:n.9C>A
ENST00000610292.4:c.832C>A
ENST00000610538.4:c.832C>A
ENST00000610623.4:c.472C>A
ENST00000615910.4:n.916C>A
ENST00000617185.4:c.949C>A
ENST00000618944.4:c.472C>A
ENST00000619186.4:c.472C>A
ENST00000619485.4:c.832C>A
ENST00000620739.4:c.832C>A
ENST00000622645.4:c.832C>A
ENST00000635293.1:c.832C>A
NM_001126112.2:c.949C>A
NM_001126113.2:c.949C>A
NM_001126114.2:c.949C>A
NM_001126115.1:c.553C>A
NM_001126116.1:c.553C>A
NM_001126117.1:c.553C>A
NM_001126118.1:c.832C>A
NM_001276695.1:c.832C>A
NM_001276696.1:c.832C>A
NM_001276697.1:c.472C>A
NM_001276698.1:c.472C>A
NM_001276699.1:c.472C>A
NM_001276760.1:c.832C>A
NM_001276761.1:c.832C>A
NM_001276695.2:c.832C>A
NM_001276696.2:c.832C>A
NM_001276697.2:c.472C>A
NM_001276698.2:c.472C>A
NM_001276699.2:c.472C>A
NM_001276760.2:c.832C>A
NM_001276761.2:c.832C>A
NM_000546.6:c.949C>A
NM_001126112.3:c.949C>A
NM_001126113.3:c.949C>A
NM_001126114.3:c.949C>A
NM_001126115.2:c.553C>A
NM_001126116.2:c.553C>A
NM_001126117.2:c.553C>A
NM_001126118.2:c.832C>A
NM_001276695.3:c.832C>A
NM_001276696.3:c.832C>A
NM_001276697.3:c.472C>A
NM_001276698.3:c.472C>A
NM_001276699.3:c.472C>A
NM_001276760.3:c.832C>A
NM_001276761.3:c.832C>A
NC_000017.11:g.7673579G>T
CM000679.2:g.7673579G>T
NC_000017.10:g.7576897G>T
CM000679.1:g.7576897G>T
NC_000017.9:g.7517622G>T
NG_017013.2:g.18972C>A

Likely Benign

Met criteria codes 3
BS2_Supporting BS3 BP4
Not Met criteria codes 15
PS3 PS1 PS2 PS4 PP3 PP1 PM2 PM6 PM1 PM5 BA1 BS1 BS4 BP5 BP2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
Transactivation assays show retained function 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; PMID: 12826609, 30224644). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting, internal laboratory contributor). In summary, TP53 c.949C>A (p.Gln317Lys) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, BS2_supporting, BP4.
Met criteria codes
BS2_Supporting
Absent from FLOSSIES database. Observed in one woman with no cancer 60+ in internal data from each of two labs, and in 4 woman with no cancer 60+ in internal data from a third lab
BS3
Kato: functional, Giacomelli: no DNE
BP4
Align-GVGD class C0, BayesDel -0.167445. No splicing effect (Varseak , SpliceAI)
Not Met criteria codes
PS3
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Seen in 1/333 Polish individuals with ovarian cancer who underwent testing for a panel of 25 genes (PMID: 30441849). Details such as histology, age of dx, FHx not reported for this individual. Seen in 1/182 Czech individuals with CLL tested for TP53 only. Details such as age of dx, FHx not reported for this individual. (PMID: 25527155) 1 germline occurrence in IARC.
PP3
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
PM2
Present in 2 European non-Finnish alleles in gnomAD v2
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
3 other missense variants in ClinVar (all classified as VUS based on absence in population databases and retention of transactivation function)
BA1
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
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2021-08-04
Published on: 2021-09-24
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