Evidence Repository - Clinical Genome Resources

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Variant: NM_000546.6(TP53):c.743G>A (p.Arg248Gln)

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CA000387

12356 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: cf887752-8539-4177-a74d-dc5c8f8a36ed

Approved on: 2024-08-05

Published on: 2024-08-05

HGVS expressions

NM_000546.6:c.743G>A

NM_000546.6(TP53):c.743G>A (p.Arg248Gln)

NC_000017.11:g.7674220C>T

CM000679.2:g.7674220C>T

NC_000017.10:g.7577538C>T

CM000679.1:g.7577538C>T

NC_000017.9:g.7518263C>T

NG_017013.2:g.18331G>A

ENST00000503591.2:c.743G>A

ENST00000508793.6:c.743G>A

ENST00000509690.6:c.347G>A

ENST00000514944.6:c.464G>A

ENST00000604348.6:c.722G>A

ENST00000269305.9:c.743G>A

ENST00000269305.8:c.743G>A

ENST00000359597.8:c.743G>A

ENST00000413465.6:c.743G>A

ENST00000420246.6:c.743G>A

ENST00000445888.6:c.743G>A

ENST00000455263.6:c.743G>A

ENST00000504290.5:c.347G>A

ENST00000504937.5:c.347G>A

ENST00000509690.5:c.347G>A

ENST00000510385.5:c.347G>A

ENST00000514944.5:c.464G>A

ENST00000610292.4:c.626G>A

ENST00000610538.4:c.626G>A

ENST00000610623.4:c.266G>A

ENST00000615910.4:c.710G>A

ENST00000617185.4:c.743G>A

ENST00000618944.4:c.266G>A

ENST00000619186.4:c.266G>A

ENST00000619485.4:c.626G>A

ENST00000620739.4:c.626G>A

ENST00000622645.4:c.626G>A

ENST00000635293.1:c.626G>A

NM_000546.5:c.743G>A

NM_001126112.2:c.743G>A

NM_001126113.2:c.743G>A

NM_001126114.2:c.743G>A

NM_001126115.1:c.347G>A

NM_001126116.1:c.347G>A

NM_001126117.1:c.347G>A

NM_001126118.1:c.626G>A

NM_001276695.1:c.626G>A

NM_001276696.1:c.626G>A

NM_001276697.1:c.266G>A

NM_001276698.1:c.266G>A

NM_001276699.1:c.266G>A

NM_001276760.1:c.626G>A

NM_001276761.1:c.626G>A

NM_001276695.2:c.626G>A

NM_001276696.2:c.626G>A

NM_001276697.2:c.266G>A

NM_001276698.2:c.266G>A

NM_001276699.2:c.266G>A

NM_001276760.2:c.626G>A

NM_001276761.2:c.626G>A

NM_001126112.3:c.743G>A

NM_001126113.3:c.743G>A

NM_001126114.3:c.743G>A

NM_001126115.2:c.347G>A

NM_001126116.2:c.347G>A

NM_001126117.2:c.347G>A

NM_001126118.2:c.626G>A

NM_001276695.3:c.626G>A

NM_001276696.3:c.626G>A

NM_001276697.3:c.266G>A

NM_001276698.3:c.266G>A

NM_001276699.3:c.266G>A

NM_001276760.3:c.626G>A

NM_001276761.3:c.626G>A

Pathogenic

PP3 PM1 PP4_Moderate PP1_Moderate PM2_Supporting PS4 PS2 PS3

PM5 BA1 BS4 BS1 BS3 BS2 BP4 PS1

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.743G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 248 (p.Arg248Gln). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly LFS-associated cancer, and in 1 individual with a moderately LFS-associated cancer totaling 7 phenotype points (PS2; PMIDs, 15381368; 35974385; 1565143). This variant has been reported in an additional two unrelated probands meeting Classic and seven probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMID: 9242456, 7887414, 36457625, 21601526, ClinVar SCV SCV000185472.8, Internal lab contributor). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in four families (PP1_Moderate; PMID: 1565143, 9242456, 7887414, 36457625). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, ClinVar GTRs, Internal lab contributors). This variant has an allele frequency of 0.000007629 (9/1179752 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1). Computational predictor scores (BayesDel = 0.4738; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4, PP1_Moderate, PP4_Moderate, PS3, PM1, PM2_Supporting, PP3. (Bayesian Points: 20; VCEP specifications version 2.0; 7/24/2024)

PP3

Computational predictor scores (BayesDel = 0.4738; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change(PP3).

PM1

This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1).

PP4_Moderate

At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, ClinVar GTRs, Internal lab contributors).

PP1_Moderate

The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in four families (PP1_Moderate; PMID: 1565143, 9242456, 7887414, 36457625).

PM2_Supporting

This variant has an allele frequency of 0.000007629 (9/1179752 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).

PS4

This variant has been reported in an additional two unrelated probands meeting Classic and seven probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMID: 9242456, 7887414, 36457625, 21601526, ClinVar SCV SCV000185472.8, Internal lab contributor).

PS2

This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly LFS-associated cancer, and in 1 individual with a moderately LFS-associated cancer totaling 7 phenotype points (PS2; PMIDs, 15381368; 35974385; 1565143).

PS3

In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3).

PM5

Two different missense variants (c.743G>C, p.Arg248Pro and c.742C>G, p.Arg248Gly) (ClinVar Variation ID 237954 and 376652) in the same codon have been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. However, these variants have higher Grantham scores and are therefore more chemically different than the c.743G>A p.Arg248Gln variant, and can not be used for PM5 weight. (PM5 not met).

BA1