Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000546.6(TP53):c.784G>A (p.Gly262Ser)

CA000416

141228 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8466fc33-68c8-4faa-b8de-23f1b6417e6d
Approved on: 2025-04-03
Published on: 2025-06-23

HGVS expressions

NM_000546.6:c.784G>A
NM_000546.6(TP53):c.784G>A (p.Gly262Ser)
NC_000017.11:g.7673836C>T
CM000679.2:g.7673836C>T
NC_000017.10:g.7577154C>T
CM000679.1:g.7577154C>T
NC_000017.9:g.7517879C>T
NG_017013.2:g.18715G>A
ENST00000503591.2:c.784G>A
ENST00000508793.6:c.784G>A
ENST00000509690.6:c.388G>A
ENST00000514944.6:c.505G>A
ENST00000604348.6:c.763G>A
ENST00000269305.9:c.784G>A
ENST00000269305.8:c.784G>A
ENST00000359597.8:c.784G>A
ENST00000413465.6:c.782+345G>A
ENST00000420246.6:c.784G>A
ENST00000445888.6:c.784G>A
ENST00000455263.6:c.784G>A
ENST00000504290.5:c.388G>A
ENST00000504937.5:c.388G>A
ENST00000509690.5:c.388G>A
ENST00000510385.5:c.388G>A
ENST00000610292.4:c.667G>A
ENST00000610538.4:c.667G>A
ENST00000610623.4:c.307G>A
ENST00000615910.4:c.751G>A
ENST00000617185.4:c.784G>A
ENST00000618944.4:c.307G>A
ENST00000619186.4:c.307G>A
ENST00000619485.4:c.667G>A
ENST00000620739.4:c.667G>A
ENST00000622645.4:c.667G>A
ENST00000635293.1:c.667G>A
NM_000546.5:c.784G>A
NM_001126112.2:c.784G>A
NM_001126113.2:c.784G>A
NM_001126114.2:c.784G>A
NM_001126115.1:c.388G>A
NM_001126116.1:c.388G>A
NM_001126117.1:c.388G>A
NM_001126118.1:c.667G>A
NM_001276695.1:c.667G>A
NM_001276696.1:c.667G>A
NM_001276697.1:c.307G>A
NM_001276698.1:c.307G>A
NM_001276699.1:c.307G>A
NM_001276760.1:c.667G>A
NM_001276761.1:c.667G>A
NM_001276695.2:c.667G>A
NM_001276696.2:c.667G>A
NM_001276697.2:c.307G>A
NM_001276698.2:c.307G>A
NM_001276699.2:c.307G>A
NM_001276760.2:c.667G>A
NM_001276761.2:c.667G>A
NM_001126112.3:c.784G>A
NM_001126113.3:c.784G>A
NM_001126114.3:c.784G>A
NM_001126115.2:c.388G>A
NM_001126116.2:c.388G>A
NM_001126117.2:c.388G>A
NM_001126118.2:c.667G>A
NM_001276695.3:c.667G>A
NM_001276696.3:c.667G>A
NM_001276697.3:c.307G>A
NM_001276698.3:c.307G>A
NM_001276699.3:c.307G>A
NM_001276760.3:c.667G>A
NM_001276761.3:c.667G>A
More

Likely Benign

Met criteria codes 3
PP3 PM2_Supporting BS2
Not Met criteria codes 14
BA1 PP4 PP1 PM1 PM5 BS4 BS3 BS1 BP2 BP4 PS2 PS4 PS3 PS1

Evidence Links 0

Expert Panel

Criteria Specification Information

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.784G>A variant in TP53 is a missense variant predicted to cause substitution of glycine by serine at amino acid 262 (p.Gly262Ser). This variant received a total of 0.5 points in one individual (PS4 not met; Internal lab contributors). 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 an allele frequency of 0.00002358 (38/1611646 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). The computational splicing predictor SpliceAI gives a score of 0.52, 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 Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, PM2_Supporting, PP3. (Bayesian Points: -2; VCEP specifications version 2.2; date of approval)
Met criteria codes
PP3
The computational splicing predictor SpliceAI gives a score of 0.52, predicting that the variant has an impact on splicing (score threshold > 0.20) (PP3)
PM2_Supporting
This variant has an allele frequency of 0.00002358 (38/1611646 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).
Not Met criteria codes
BA1
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
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 (p.Gly262Asp, p.Gly262Val, p.Gly262Arg) in the same codon have been reported (ClinVar Variation IDs: 2993845, 428889, 1760888). However, these variants do not meet criteria for PM5 code application (PM5 not met).
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
BS1
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
BP4
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
PS4
This variant received a total of 0.5 points in one individual (PS4 not met; Internal lab contributors).
PS3
Functional codes not to be used when PP3 is applied for based on SpliceAI
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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