Variant: NM_001276761.2:c.-72C>A

CA397849034

1172924 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 293a5c7a-2593-4a7d-afc2-9e06636238fe

Approved on: 2025-02-06

Published on: 2025-02-07

HGVS expressions

NM_001276761.2:c.-72C>A
NC_000017.11:g.7676549G>T
CM000679.2:g.7676549G>T
NC_000017.10:g.7579867G>T
CM000679.1:g.7579867G>T
NC_000017.9:g.7520592G>T
NG_017013.2:g.16002C>A
ENST00000503591.2:c.46C>A
ENST00000508793.6:c.46C>A
ENST00000509690.6:c.-21-1313C>A
ENST00000514944.6:c.46C>A
ENST00000604348.6:c.46C>A
ENST00000269305.9:c.46C>A
ENST00000269305.8:c.46C>A
ENST00000359597.8:c.46C>A
ENST00000413465.6:c.46C>A
ENST00000420246.6:c.46C>A
ENST00000445888.6:c.46C>A
ENST00000455263.6:c.46C>A
ENST00000503591.1:c.46C>A
ENST00000505014.5:n.185C>A
ENST00000508793.5:c.46C>A
ENST00000509690.5:c.-21-1313C>A
ENST00000514944.5:c.46C>A
ENST00000604348.5:c.46C>A
ENST00000610292.4:c.-189C>A
ENST00000610538.4:c.-72C>A
ENST00000615910.4:c.46C>A
ENST00000617185.4:c.46C>A
ENST00000619485.4:c.-72C>A
ENST00000620739.4:c.-72C>A
ENST00000622645.4:c.-72C>A
ENST00000635293.1:c.-72C>A
NM_000546.5:c.46C>A
NM_001126112.2:c.46C>A
NM_001126113.2:c.46C>A
NM_001126114.2:c.46C>A
NM_001126118.1:c.-189C>A
NM_001276695.1:c.-72C>A
NM_001276696.1:c.-72C>A
NM_001276760.1:c.-72C>A
NM_001276761.1:c.-72C>A
NM_001276695.2:c.-72C>A
NM_001276696.2:c.-72C>A
NM_001276760.2:c.-72C>A
NM_000546.6:c.46C>A
NM_001126112.3:c.46C>A
NM_001126113.3:c.46C>A
NM_001126114.3:c.46C>A
NM_001126118.2:c.-189C>A
NM_001276695.3:c.-72C>A
NM_001276696.3:c.-72C>A
NM_001276760.3:c.-72C>A
NM_001276761.3:c.-72C>A

Uncertain Significance

• Met criteria codes: PP3 PM2_Supporting

• Not Met criteria codes: BA1 PP1 PM5 PM1 PM6 BS4 BS3 BS1 BS2 BP2 BP4 PS2 PS4 PS1 PS3

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.2.0

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6:c.46C>A variant in TP53 is a missense variant predicted to cause substitution of glutamine by lysine at amino acid 16 (p.Gln16Lys). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; PMID:34196900) This variant is absent from gnomAD v4.1.0 (PM2_Supporting). BS3 met but not applied due to caveat that functional codes not be applied to any missense variant that has splicing effect on SpliceAI where PP3 is applied. The computational splicing predictor SpliceAI gives a score of 0.84, predicting that the variant has an impact on splicing (score threshold > 0.20) (PP3). In summary, this variant meets the criteria to be classified as variant of uncertain significance for Li-Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, PP3. (Bayesian Points: 2; VCEP specifications version 2.2; 2/6/2025).

Met criteria codes

• PP3: The computational splicing predictor SpliceAI gives a score of 0.84, predicting that the variant has an impact on splicing (score threshold > 0.20) (PP3).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No reports in literature or internal data
• PM5: Two other variants in ClinVar, both VUS
• PM1: This variant does not reside within a region of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1 not met).
• PM6: No reports in literature or internal data
• BS4: No reports in literature or internal data
• BS3: BS3 not applied due to caveat that functional codes not be applied to any missense variant that has splicing effect on SpliceAI where PP3 is applied. 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: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: Not in FLOSSIES
• BP2: No reports in literature or internal data
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No reports in literature or internal data
• PS4: Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; PMID:34196900)
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline