Variant: NM_000546.6(TP53):c.85_87AAC[1] (p.Asn30del)

CA358484

142158 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 7d2cb855-34af-45fd-82a4-737b107f9814

Approved on: 2025-04-03

Published on: 2025-06-23

HGVS expressions

NM_000546.6:c.85_87AAC[1]
NM_000546.6(TP53):c.85_87AAC[1] (p.Asn30del)
NC_000017.11:g.7676391_7676393del
CM000679.2:g.7676391_7676393del
NC_000017.10:g.7579709_7579711del
CM000679.1:g.7579709_7579711del
NC_000017.9:g.7520434_7520436del
NG_017013.2:g.16161_16163del
ENST00000503591.2:c.88_90del
ENST00000508793.6:c.88_90del
ENST00000509690.6:c.-21-1154_-21-1152del
ENST00000514944.6:c.88_90del
ENST00000604348.6:c.88_90del
ENST00000269305.9:c.88_90del
ENST00000269305.8:c.88_90del
ENST00000359597.8:c.88_90del
ENST00000413465.6:c.88_90del
ENST00000420246.6:c.88_90del
ENST00000445888.6:c.88_90del
ENST00000455263.6:c.88_90del
ENST00000503591.1:c.88_90del
ENST00000505014.5:n.344_346del
ENST00000508793.5:c.88_90del
ENST00000509690.5:c.-21-1154_-21-1152del
ENST00000514944.5:c.88_90del
ENST00000604348.5:c.88_90del
ENST00000610292.4:c.-30_-28del
ENST00000610538.4:c.-30_-28del
ENST00000615910.4:c.88_90del
ENST00000617185.4:c.88_90del
ENST00000619485.4:c.-30_-28del
ENST00000620739.4:c.-30_-28del
ENST00000622645.4:c.-30_-28del
ENST00000635293.1:c.-30_-28del
NM_000546.5:c.88_90del
NM_001126112.2:c.88_90del
NM_001126113.2:c.88_90del
NM_001126114.2:c.88_90del
NM_001126118.1:c.-30_-28del
NM_001276695.1:c.-30_-28del
NM_001276696.1:c.-30_-28del
NM_001276760.1:c.-30_-28del
NM_001276761.1:c.-30_-28del
NM_001276695.2:c.-30_-28del
NM_001276696.2:c.-30_-28del
NM_001276760.2:c.-30_-28del
NM_001276761.2:c.-30_-28del
NM_000546.6:c.88_90del
NM_001126112.3:c.88_90del
NM_001126113.3:c.88_90del
NM_001126114.3:c.88_90del
NM_001126118.2:c.-30_-28del
NM_001276695.3:c.-30_-28del
NM_001276696.3:c.-30_-28del
NM_001276760.3:c.-30_-28del
NM_001276761.3:c.-30_-28del

Likely Benign

• Met criteria codes: PM2_Supporting BS2 BP4 PP1 PS4_Supporting

• Not Met criteria codes: BA1 BS1 BS4 BS3 BP1 BP2 BP5 PS1 PS2 PS3 PP2 PP3 PP4 PM1 PM3 PM5 PM6

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.3.0

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6: c.85_87AAC variant in TP53 is an AAC deletion at nucleotide positions 88 to 90 predicted to cause an in-frame deletion of asparagine at amino acid 30 (p.Asn30del). 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; Internal lab contributor). This variant has been reported in 2 unrelated probands/families meeting Revised Chompret criteria and reported in 1 additional individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMIDs, ClinVar SCVs, Internal lab contributors). The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; Internal lab contributors). This variant has an allele frequency of 0.0000006197 (1/1613566 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). Computational predictor score (BayesDel = -0.83349) is below the recommended threshold (BayesDel < 0.16), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant is classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, PS4_Supporting, PP1, PM2_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 2.3)

Met criteria codes

• PM2_Supporting: This variant has an allele frequency of 0.0000006197 (1/1613566 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting).
• 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; Internal lab contributor).
• BP4: Computational predictor score (BayesDel = -0.83349) is below the recommended threshold (BayesDel < 0.16), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4).
• PP1: The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; Internal lab contributors).
• PS4_Supporting: This variant has been reported in 2 unrelated probands/families meeting Revised Chompret criteria and reported in 1 additional individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMIDs, ClinVar SCVs, Internal lab contributors).

Not Met criteria codes

• 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
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: 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
• BP5: 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
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: 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
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline