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NM_000546.6(TP53):c.830G>T (p.Cys277Phe) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Feb 25, 2025
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002431551.5

Allele description [Variation Report for NM_000546.6(TP53):c.830G>T (p.Cys277Phe)]

NM_000546.6(TP53):c.830G>T (p.Cys277Phe)

Gene:
TP53:tumor protein p53 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17p13.1
Genomic location:
Preferred name:
NM_000546.6(TP53):c.830G>T (p.Cys277Phe)
HGVS:
  • NC_000017.11:g.7673790C>A
  • NG_017013.2:g.18761G>T
  • NM_000546.6:c.830G>TMANE SELECT
  • NM_001126112.3:c.830G>T
  • NM_001126113.3:c.830G>T
  • NM_001126114.3:c.830G>T
  • NM_001126115.2:c.434G>T
  • NM_001126116.2:c.434G>T
  • NM_001126117.2:c.434G>T
  • NM_001126118.2:c.713G>T
  • NM_001276695.3:c.713G>T
  • NM_001276696.3:c.713G>T
  • NM_001276697.3:c.353G>T
  • NM_001276698.3:c.353G>T
  • NM_001276699.3:c.353G>T
  • NM_001276760.3:c.713G>T
  • NM_001276761.3:c.713G>T
  • NP_000537.3:p.Cys277Phe
  • NP_000537.3:p.Cys277Phe
  • NP_001119584.1:p.Cys277Phe
  • NP_001119585.1:p.Cys277Phe
  • NP_001119586.1:p.Cys277Phe
  • NP_001119587.1:p.Cys145Phe
  • NP_001119588.1:p.Cys145Phe
  • NP_001119589.1:p.Cys145Phe
  • NP_001119590.1:p.Cys238Phe
  • NP_001263624.1:p.Cys238Phe
  • NP_001263625.1:p.Cys238Phe
  • NP_001263626.1:p.Cys118Phe
  • NP_001263627.1:p.Cys118Phe
  • NP_001263628.1:p.Cys118Phe
  • NP_001263689.1:p.Cys238Phe
  • NP_001263690.1:p.Cys238Phe
  • LRG_321t1:c.830G>T
  • LRG_321:g.18761G>T
  • LRG_321p1:p.Cys277Phe
  • NC_000017.10:g.7577108C>A
  • NM_000546.4:c.830G>T
  • NM_000546.5:c.830G>T
Protein change:
C118F
Links:
dbSNP: rs763098116
NCBI 1000 Genomes Browser:
rs763098116
Molecular consequence:
  • NM_000546.6:c.830G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.3:c.830G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.3:c.830G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.3:c.830G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126115.2:c.434G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126116.2:c.434G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126117.2:c.434G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.2:c.713G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.3:c.713G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.3:c.713G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276697.3:c.353G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276698.3:c.353G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276699.3:c.353G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.3:c.713G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.3:c.713G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Hereditary neoplastic syndrome; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002679241Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Feb 25, 2025) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV005402577Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
criteria provided, single submitter

(Dawood et al. (medRxiv. 2024))		Likely pathogenic
(Apr 12, 2024) 		germlinecuration

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

Citations

PubMed

Influence of p53 mutations on prognosis of patients with glioblastoma.

Shiraishi S, Tada K, Nakamura H, Makino K, Kochi M, Saya H, Kuratsu J, Ushio Y.

Cancer. 2002 Jul 15;95(2):249-57.

PubMed [citation]
PMID:
12124823

Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.

Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R, Ishioka C.

Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8424-9. Epub 2003 Jun 25.

PubMed [citation]
PMID:
12826609
PMCID:
PMC166245
See all PubMed Citations (10)

Details of each submission

From Ambry Genetics, SCV002679241.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

The p.C277F pathogenic mutation (also known as c.830G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 830. The cysteine at codon 277 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been shown to have a loss of transactivation activity in yeast based functional studies (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. U.S.A., 2003 Jul;100:8424-9; Kucab JE et al. DNA Repair (Amst.), 2016 Mar;39:21-33; Paget V et al. PLoS ONE, 2012 Feb;7:e30921). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Another alteration at the same codon, p.C277R (c.829T>C), has been detected an individual with a personal history of adrenocortical carcinoma and shown to segregate with disease in three affected family members in one family with early-onset breast cancer tested by our laboratory (Ambry internal data). This amino acid position is well conserved in available vertebrate species. The p.C277F alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD) non-cancer dataset. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine, SCV005402577.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (3)

Description

Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).For TP53, we used the output of the Naïve Bayes classifier that synthesized data from four different TP53 MAVEs in Fayer et al. (2021) (PMID: 34793697). If the classifier predicted a variant to be "Functionally abnormal," the variant was assigned PS3 evidence and no BS3 evidence. If a variant was predicted to be "Functionally normal," BS3_moderate evidence was used with no PS3 evidence. This variant GRCh38:17:7673790:C>A was assigned evidence codes ['PS3', 'PP3_Moderate'] and an overall classification of Likely pathogenic

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 16, 2025