Variant: NM_000546.5(TP53):c.393C>A (p.Asn131Lys)

CA002656

246429 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 3147e5cd-492f-4b46-9227-de2572c8bc19

Approved on: 2025-02-06

Published on: 2025-02-07

HGVS expressions

NM_000546.5:c.393C>A
NM_000546.5(TP53):c.393C>A (p.Asn131Lys)
NC_000017.11:g.7675219G>T
CM000679.2:g.7675219G>T
NC_000017.10:g.7578537G>T
CM000679.1:g.7578537G>T
NC_000017.9:g.7519262G>T
NG_017013.2:g.17332C>A
ENST00000503591.2:c.393C>A
ENST00000508793.6:c.393C>A
ENST00000509690.6:c.-4C>A
ENST00000514944.6:c.114C>A
ENST00000604348.6:c.376-4C>A
ENST00000269305.9:c.393C>A
ENST00000269305.8:c.393C>A
ENST00000359597.8:c.393C>A
ENST00000413465.6:c.393C>A
ENST00000420246.6:c.393C>A
ENST00000445888.6:c.393C>A
ENST00000455263.6:c.393C>A
ENST00000504290.5:c.-4C>A
ENST00000504937.5:c.-4C>A
ENST00000505014.5:n.649C>A
ENST00000508793.5:c.393C>A
ENST00000509690.5:c.-4C>A
ENST00000510385.5:c.-4C>A
ENST00000514944.5:c.114C>A
ENST00000604348.5:c.376-4C>A
ENST00000610292.4:c.276C>A
ENST00000610538.4:c.276C>A
ENST00000610623.4:c.-85C>A
ENST00000615910.4:c.360C>A
ENST00000617185.4:c.393C>A
ENST00000618944.4:c.-85C>A
ENST00000619186.4:c.-85C>A
ENST00000619485.4:c.276C>A
ENST00000620739.4:c.276C>A
ENST00000622645.4:c.276C>A
ENST00000635293.1:c.276C>A
NM_001126112.2:c.393C>A
NM_001126113.2:c.393C>A
NM_001126114.2:c.393C>A
NM_001126115.1:c.-4C>A
NM_001126116.1:c.-4C>A
NM_001126117.1:c.-4C>A
NM_001126118.1:c.276C>A
NM_001276695.1:c.276C>A
NM_001276696.1:c.276C>A
NM_001276697.1:c.-85C>A
NM_001276698.1:c.-85C>A
NM_001276699.1:c.-85C>A
NM_001276760.1:c.276C>A
NM_001276761.1:c.276C>A
NM_001276695.2:c.276C>A
NM_001276696.2:c.276C>A
NM_001276697.2:c.-85C>A
NM_001276698.2:c.-85C>A
NM_001276699.2:c.-85C>A
NM_001276760.2:c.276C>A
NM_001276761.2:c.276C>A
NM_000546.6:c.393C>A
NM_001126112.3:c.393C>A
NM_001126113.3:c.393C>A
NM_001126114.3:c.393C>A
NM_001126115.2:c.-4C>A
NM_001126116.2:c.-4C>A
NM_001126117.2:c.-4C>A
NM_001126118.2:c.276C>A
NM_001276695.3:c.276C>A
NM_001276696.3:c.276C>A
NM_001276697.3:c.-85C>A
NM_001276698.3:c.-85C>A
NM_001276699.3:c.-85C>A
NM_001276760.3:c.276C>A
NM_001276761.3:c.276C>A

Uncertain Significance

• Met criteria codes: BS3_Supporting PS4_Moderate PM2_Supporting BS2_Supporting

• Not Met criteria codes: BP7 BP4 BS4 BS1 PP4 PP1 PP3 PS2 PS3 PS1 PM1 PM5 PVS1 BA1

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.393C>A variant in TP53 is a missense variant predicted to cause substitution of asparagine by lysine at amino acid 131 (p.Asn131Lys). This variant has been reported in 3 unrelated families] meeting Revised Chompret criteria with one of these cases including an individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 2 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; Internal lab contributors). This variant has been observed in 2-3 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_Supporting; Internal lab contributors). This variant has an allele frequency of 0.000008055 (13/1613958 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). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Due to conflicting evidence, this variant is classified as a variant of unknown significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Moderate, BS2_Supporting, PM2_Supporting, BS3_Supporting. (Bayesian Points: 1; VCEP specifications version 2.2; 2/6/2025)

Met criteria codes

• BS3_Supporting: In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644).
• PS4_Moderate: This variant has been reported in 3 unrelated families meeting Revised Chompret criteria with one of these cases including an individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 2 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; Internal lab contributors).
• PM2_Supporting: This variant has an allele frequency of 0.000008055 (13/1613958 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_Supporting: This variant has been observed in 2-3 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_Supporting; Internal lab contributors).

Not Met criteria codes

• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: The results from the computational predictors BayesDel and AlignGVGD do not agree, providing no evidence that correlates with a damaging or benign impact on TP53 function via protein change. Additionally, SpliceAI predicts that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met).
• BS4: 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
• PP4: 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
• PP3: The results from the computational predictors BayesDel and AlignGVGD do not agree, providing no evidence that correlates with a damaging or benign impact on TP53 function via protein change. Additionally, SpliceAI predicts that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met).
• 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
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• 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).
• PM5: 3 different missense variants (c.392A>T, p.Asn131Ile; c.392A>G, p.Asn131Ser; c.391A>T, p.Asn131Tyr) in the same codon have been reported (ClinVar Variation ID 428902, 1057941, 141988). However, this variant does not meet criteria for PM5 code application (PM5 not met).
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline