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_000546.5(TP53):c.554G>A (p.Ser185Asn)

CA000264

141359 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1febb627-e7ab-467a-9101-1ee37ceccf6a

Approved on: 2020-09-04

Published on: 2020-09-04

HGVS expressions

NM_000546.5:c.554G>A

NM_000546.5(TP53):c.554G>A (p.Ser185Asn)

NM_001126112.2:c.554G>A

NM_001126113.2:c.554G>A

NM_001126114.2:c.554G>A

NM_001126115.1:c.158G>A

NM_001126116.1:c.158G>A

NM_001126117.1:c.158G>A

NM_001126118.1:c.437G>A

NM_001276695.1:c.437G>A

NM_001276696.1:c.437G>A

NM_001276697.1:c.77G>A

NM_001276698.1:c.77G>A

NM_001276699.1:c.77G>A

NM_001276760.1:c.437G>A

NM_001276761.1:c.437G>A

NM_001276695.2:c.437G>A

NM_001276696.2:c.437G>A

NM_001276697.2:c.77G>A

NM_001276698.2:c.77G>A

NM_001276699.2:c.77G>A

NM_001276760.2:c.437G>A

NM_001276761.2:c.437G>A

ENST00000269305.8:c.554G>A

ENST00000359597.8:n.554G>A

ENST00000413465.6:n.554G>A

ENST00000420246.6:c.554G>A

ENST00000445888.6:c.554G>A

ENST00000455263.6:c.554G>A

ENST00000504290.5:c.158G>A

ENST00000504937.5:c.158G>A

ENST00000505014.5:n.810G>A

ENST00000509690.5:c.158G>A

ENST00000510385.5:c.158G>A

ENST00000514944.5:c.275G>A

ENST00000574684.1:n.62G>A

ENST00000610292.4:c.437G>A

ENST00000610538.4:c.437G>A

ENST00000610623.4:c.77G>A

ENST00000615910.4:n.521G>A

ENST00000617185.4:c.554G>A

ENST00000618944.4:c.77G>A

ENST00000619186.4:c.77G>A

ENST00000619485.4:c.437G>A

ENST00000620739.4:c.437G>A

ENST00000622645.4:c.437G>A

ENST00000635293.1:c.437G>A

NC_000017.11:g.7675058C>T

CM000679.2:g.7675058C>T

NC_000017.10:g.7578376C>T

CM000679.1:g.7578376C>T

NC_000017.9:g.7519101C>T

NG_017013.2:g.17493G>A

Likely Benign

BS3 BP4

BS2 BS1 BS4 BP2 BP7 PM5 PM1 PS1 PS3 PS4 PS2 BA1 PM6 PVS1 PP3 PP1

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 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). In summary, TP53 c.554G>A (p.Ser185Asn) 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, BP4.

BS3

Kato assay: functional (mean 98.6 activity) Giacomelli: notDNE_notLOF Kotler score: -2.883 (not LOF>-1)

PubMed:30224644

PubMed:12826609

PubMed:29979965

BP4

Align-GVGD = Class C0; BayesDel = -0.159418

BS2

FLOSSIES: Found in one individual in FLOSSIES (women > 70 years old). No internal lab data with females unaffected at or over age 60

BS1

There is one allele of African origin in gnomAD v2.1.1 non cancer subset (global allele frequency = 0.000004223; 1/236814)

BS4

No data available

BP2

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

BP7

Missense variant

PM5

There is no variant in residue S185 determined to be pathogenic by the ClinGen TP53 Expert Panel.

PM1

Codon 185 is not considered a hotspot. Cancerhotspots.org does not include somatic observations for S185N (no occurence for S185, regardless of aminoacid change)

PS1

There is no previously established pathogenic variant p.S185N with a different nucleotide change. According to the IARC database, the variant generates a broken acceptor splice site (HSF_V2.3)

PS3

Kato assay: functional (mean 98.6 activity) Giacomelli: notDNE_notLOF Kotler score: -2.883 (not LOF>-1)

PS4

-PMID 25896519: one osteosarcoma case (unique case also reported to IARC). No information on age at diagnosis or family history = 0 points. -No internal lab data with confirmed Revised Chompret or Classical cases. One internal lab case with individual who meets Revised Chompret with breast cancer diagnosis also carrying a splicing BRCA mutation so not used. Total points with available data: 0.5 (not enough to score PS4)

PubMed:25896519

PS2

No data available

BA1

There is one allele of African origin in gnomAD v2.1.1 non cancer subset (global allele frequency = 0.000004223; 1/236814)

PM6

No data available

PVS1

Missense variant

PP3

Align-GVGD = Class C0; BayesDel = -0.159418

PP1

No data available

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