Variant: NM_001276761.2:c.365_370del

CA915940817

973858 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 04670dbf-dcc3-4cec-8727-691d183eec54

Approved on: 2024-09-06

Published on: 2024-09-06

HGVS expressions

NM_001276761.2:c.365_370del
NC_000017.11:g.7675125_7675130del
CM000679.2:g.7675125_7675130del
NC_000017.10:g.7578443_7578448del
CM000679.1:g.7578443_7578448del
NC_000017.9:g.7519168_7519173del
NG_017013.2:g.17421_17426del
ENST00000503591.2:c.482_487del
ENST00000508793.6:c.482_487del
ENST00000509690.6:c.86_91del
ENST00000514944.6:c.203_208del
ENST00000604348.6:c.461_466del
ENST00000269305.9:c.482_487del
ENST00000269305.8:c.482_487del
ENST00000359597.8:c.482_487del
ENST00000413465.6:c.482_487del
ENST00000420246.6:c.482_487del
ENST00000445888.6:c.482_487del
ENST00000455263.6:c.482_487del
ENST00000504290.5:c.86_91del
ENST00000504937.5:c.86_91del
ENST00000505014.5:n.738_743del
ENST00000508793.5:c.482_487del
ENST00000509690.5:c.86_91del
ENST00000510385.5:c.86_91del
ENST00000514944.5:c.203_208del
ENST00000610292.4:c.365_370del
ENST00000610538.4:c.365_370del
ENST00000610623.4:c.5_10del
ENST00000615910.4:c.449_454del
ENST00000617185.4:c.482_487del
ENST00000618944.4:c.5_10del
ENST00000619186.4:c.5_10del
ENST00000619485.4:c.365_370del
ENST00000620739.4:c.365_370del
ENST00000622645.4:c.365_370del
ENST00000635293.1:c.365_370del
NM_000546.5:c.482_487del
NM_001126112.2:c.482_487del
NM_001126113.2:c.482_487del
NM_001126114.2:c.482_487del
NM_001126115.1:c.86_91del
NM_001126116.1:c.86_91del
NM_001126117.1:c.86_91del
NM_001126118.1:c.365_370del
NM_001276695.1:c.365_370del
NM_001276696.1:c.365_370del
NM_001276697.1:c.5_10del
NM_001276698.1:c.5_10del
NM_001276699.1:c.5_10del
NM_001276760.1:c.365_370del
NM_001276761.1:c.365_370del
NM_001276695.2:c.365_370del
NM_001276696.2:c.365_370del
NM_001276697.2:c.5_10del
NM_001276698.2:c.5_10del
NM_001276699.2:c.5_10del
NM_001276760.2:c.365_370del
NM_000546.6:c.482_487del
NM_001126112.3:c.482_487del
NM_001126113.3:c.482_487del
NM_001126114.3:c.482_487del
NM_001126115.2:c.86_91del
NM_001126116.2:c.86_91del
NM_001126117.2:c.86_91del
NM_001126118.2:c.365_370del
NM_001276695.3:c.365_370del
NM_001276696.3:c.365_370del
NM_001276697.3:c.5_10del
NM_001276698.3:c.5_10del
NM_001276699.3:c.5_10del
NM_001276760.3:c.365_370del
NM_001276761.3:c.365_370del

Likely Pathogenic

• Met criteria codes: PP1 PM5 PM1_Supporting PM2_Supporting PS4_Supporting

• Not Met criteria codes: BS2 BS4 BS1 BP4 PS1 PS2 PP4 PP3 BA1 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 2.0.0

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6:c.482_487del variant is predicted to cause a change in the length of the protein (p.Ala161_Tyr163delinsAsp) due to an in-frame deletion of 3 amino acids and insertion of 1 amino acid. This variant has been reported in 1 family meeting Classic Li-Fraumeni syndrome criteria. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal contributors). The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; Internal contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The individual missense variants, A161D and Y163D, used as proxies for this indel variant have 7 and 3 somatic occurrences, respectively, for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). Another missense variant (c.488A>G, p.Tyr163Cys) (ClinVar Variation ID: 127814), in an involved codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications (PM5). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Supporting, PP1, PM2_Supporting, PM1_Supporting, PM5. (Bayesian Points: 6; VCEP specifications version 2.0; 9/6/2024)

Met criteria codes

• PP1: The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; Internal contributors).
• PM5: Another missense variant (c.488A>G, p.Tyr163Cys) (ClinVar Variation ID: 127814), in the same codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). Although, this variant is not a missense variant, the VCEP felt that PM5 would still apply in this case.
• PM1_Supporting: Not a missense variant. However, the VCEP felt that consideration of the constituent "missense" variants making up this variant could count toward PM1. The individual missense variants, A161D and Y163D, used as a proxy for this indel variant have 7 and 3 somatic occurrences, respectively, for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
• PS4_Supporting: This variant has been reported in 1 family meeting Classic criteria. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal contributors). Contributors: Hopkins, Invitae

Not Met criteria codes

• BS2: Not found in FLOSSIES
• BS4: No cases in the literature
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: Not applicable for small deletion insertion variants.
• PS1: This variant is not a missense variant; therefore, PS1 does not apply.
• PS2: No de novo cases found
• PP4: No low VAF observations reported.
• PP3: Not applicable for small deletion insertion variants.
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No de novo cases found