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.935C>G (p.Thr312Ser)

CA000505

141102 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: c3655e4d-7f5e-4830-b702-3893ec9be6ac

Approved on: 2024-08-05

Published on: 2024-08-05

HGVS expressions

NM_000546.5:c.935C>G

NM_000546.5(TP53):c.935C>G (p.Thr312Ser)

NC_000017.11:g.7673593G>C

CM000679.2:g.7673593G>C

NC_000017.10:g.7576911G>C

CM000679.1:g.7576911G>C

NC_000017.9:g.7517636G>C

NG_017013.2:g.18958C>G

ENST00000503591.2:c.935C>G

ENST00000508793.6:c.935C>G

ENST00000509690.6:c.539C>G

ENST00000514944.6:c.656C>G

ENST00000604348.6:c.914C>G

ENST00000269305.9:c.935C>G

ENST00000269305.8:c.935C>G

ENST00000359597.8:c.935C>G

ENST00000413465.6:c.782+588C>G

ENST00000420246.6:c.935C>G

ENST00000445888.6:c.935C>G

ENST00000455263.6:c.935C>G

ENST00000504290.5:c.539C>G

ENST00000504937.5:c.539C>G

ENST00000509690.5:c.539C>G

ENST00000510385.5:c.539C>G

ENST00000610292.4:c.818C>G

ENST00000610538.4:c.818C>G

ENST00000610623.4:c.458C>G

ENST00000615910.4:c.902C>G

ENST00000617185.4:c.935C>G

ENST00000618944.4:c.458C>G

ENST00000619186.4:c.458C>G

ENST00000619485.4:c.818C>G

ENST00000620739.4:c.818C>G

ENST00000622645.4:c.818C>G

ENST00000635293.1:c.818C>G

NM_001126112.2:c.935C>G

NM_001126113.2:c.935C>G

NM_001126114.2:c.935C>G

NM_001126115.1:c.539C>G

NM_001126116.1:c.539C>G

NM_001126117.1:c.539C>G

NM_001126118.1:c.818C>G

NM_001276695.1:c.818C>G

NM_001276696.1:c.818C>G

NM_001276697.1:c.458C>G

NM_001276698.1:c.458C>G

NM_001276699.1:c.458C>G

NM_001276760.1:c.818C>G

NM_001276761.1:c.818C>G

NM_001276695.2:c.818C>G

NM_001276696.2:c.818C>G

NM_001276697.2:c.458C>G

NM_001276698.2:c.458C>G

NM_001276699.2:c.458C>G

NM_001276760.2:c.818C>G

NM_001276761.2:c.818C>G

NM_000546.6:c.935C>G

NM_001126112.3:c.935C>G

NM_001126113.3:c.935C>G

NM_001126114.3:c.935C>G

NM_001126115.2:c.539C>G

NM_001126116.2:c.539C>G

NM_001126117.2:c.539C>G

NM_001126118.2:c.818C>G

NM_001276695.3:c.818C>G

NM_001276696.3:c.818C>G

NM_001276697.3:c.458C>G

NM_001276698.3:c.458C>G

NM_001276699.3:c.458C>G

NM_001276760.3:c.818C>G

NM_001276761.3:c.818C>G

Benign

BS2 BS3 BS1 BP4

BS4 BP3 BP7 PM1 PM4 PM5 PS2 PS4 PS1 PS3 BA1 PVS1 PM2 PP4 PP1 PP3

Evidence Links 0

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6 :c.935C>G variant in TP53 is a missense variant predicted to cause substitution of threonine by serine at amino acid 312 (p.Thr312Ser). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; SCV000261663, SCV000184232). The filtering allele frequency is 0.0003446 in the African/African American population in gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.0003 but <0.001) for BS1, and therefore meets this criterion (BS1). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.0123; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS1, BS3, BP4_moderate. (Bayesian Points: -14; VCEP specifications version 2.0; 7/24/2024)

BS2

This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; SCV000261663, SCV000184232).

BS3

In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644).

BS1

The filtering allele frequency is 0.0003446 in the African/African American population in gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.0003 but <0.001) for BS1, and therefore meets this criterion (BS1).

BP4

BP4_MODERATE Computational predictor scores (BayesDel = -0.0123; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate).

BS4