NM_000546.5(TP53):c.917G>A (p.Arg306Gln) AND Li-Fraumeni syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Feb 15, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000527123.5

Allele description [Variation Report for NM_000546.5(TP53):c.917G>A (p.Arg306Gln)]

NM_000546.5(TP53):c.917G>A (p.Arg306Gln)

Gene:
TP53:tumor protein p53 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17p13.1
Genomic location:
Preferred name:
NM_000546.5(TP53):c.917G>A (p.Arg306Gln)
HGVS:
  • NC_000017.11:g.7673703C>T
  • NG_017013.2:g.18848G>A
  • NM_000546.5:c.917G>A
  • NM_001126112.2:c.917G>A
  • NM_001126113.2:c.917G>A
  • NM_001126114.2:c.917G>A
  • NM_001126115.1:c.521G>A
  • NM_001126116.1:c.521G>A
  • NM_001126117.1:c.521G>A
  • NM_001126118.1:c.800G>A
  • NM_001276695.2:c.800G>A
  • NM_001276696.2:c.800G>A
  • NM_001276697.2:c.440G>A
  • NM_001276698.2:c.440G>A
  • NM_001276699.2:c.440G>A
  • NM_001276760.2:c.800G>A
  • NM_001276761.2:c.800G>A
  • NP_000537.3:p.Arg306Gln
  • NP_001119584.1:p.Arg306Gln
  • NP_001119585.1:p.Arg306Gln
  • NP_001119586.1:p.Arg306Gln
  • NP_001119587.1:p.Arg174Gln
  • NP_001119588.1:p.Arg174Gln
  • NP_001119589.1:p.Arg174Gln
  • NP_001119590.1:p.Arg267Gln
  • NP_001263624.1:p.Arg267Gln
  • NP_001263625.1:p.Arg267Gln
  • NP_001263626.1:p.Arg147Gln
  • NP_001263627.1:p.Arg147Gln
  • NP_001263628.1:p.Arg147Gln
  • NP_001263689.1:p.Arg267Gln
  • NP_001263690.1:p.Arg267Gln
  • LRG_321t1:c.917G>A
  • LRG_321t2:c.917G>A
  • LRG_321t3:c.917G>A
  • LRG_321t4:c.917G>A
  • LRG_321t5:c.521G>A
  • LRG_321t6:c.521G>A
  • LRG_321t7:c.521G>A
  • LRG_321t8:c.800G>A
  • LRG_321:g.18848G>A
  • LRG_321:p.Arg306Gln
  • LRG_321p1:p.Arg306Gln
  • LRG_321p3:p.Arg306Gln
  • LRG_321p4:p.Arg306Gln
  • LRG_321p5:p.Arg174Gln
  • LRG_321p6:p.Arg174Gln
  • LRG_321p7:p.Arg174Gln
  • LRG_321p8:p.Arg267Gln
  • NC_000017.10:g.7577021C>T
  • NM_000546.4:c.917G>A
Protein change:
R147Q
Links:
dbSNP: rs1048095040
NCBI 1000 Genomes Browser:
rs1048095040
Molecular consequence:
  • NM_000546.5:c.917G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.2:c.917G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.2:c.917G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.2:c.917G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126115.1:c.521G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126116.1:c.521G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126117.1:c.521G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.1:c.800G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.2:c.800G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.2:c.800G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276697.2:c.440G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276698.2:c.440G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276699.2:c.440G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.2:c.800G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.2:c.800G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Li-Fraumeni syndrome (LFS)
Synonyms:
Sarcoma family syndrome of Li and Fraumeni
Identifiers:
MONDO: MONDO:0018875; MedGen: C0085390; OMIM: PS151623

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000629886Invitaecriteria provided, single submitter
Uncertain significance
(Feb 15, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000788228University of Washington Department of Laboratory Medicine, University of Washingtoncriteria provided, single submitter
Likely benign
(Mar 28, 2018)
germlineresearch

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenonot provided1not providednot providednoresearch

Citations

PubMed

Beyond BRCA1 and BRCA2 wild-type breast and/or ovarian cancer families: germline mutations in TP53 and PTEN.

Blanco A, Graña B, Fachal L, Santamariña M, Cameselle-Teijeiro J, Ruíz-Ponte C, Carracedo A, Vega A.

Clin Genet. 2010 Feb;77(2):193-6. doi: 10.1111/j.1399-0004.2009.01309.x. Epub 2009 Nov 23. No abstract available.

PubMed [citation]
PMID:
19930417

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 (4)

Details of each submission

From Invitae, SCV000629886.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces arginine with glutamine at codon 306 of the TP53 protein (p.Arg306Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with ovarian cancer (PMID: 19930417) and breast cancer (PMID: 30374176). ClinVar contains an entry for this variant (Variation ID: 458574). An experimental study in yeast has shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From University of Washington Department of Laboratory Medicine, University of Washington, SCV000788228.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednoresearch PubMed (1)

Description

The TP53 variant designated as NM_000546.5:c.917G>A (p.Arg306Gln) is classified as likely benign in the context of Li-Fraumeni syndrome. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and gives a likelihood ratio of less than 0.05 to 1 (Thompson et al., 2013, PMID:12900794) in the context of Li-Fraumeni syndrome. This indicates that the TP53 variant is very unlikely to increase the risks of cancer to the extent reported in Li-Fraumeni syndrome. The variant is at a moderately conserved genomic position. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a <1% probability of pathogenicity, which is consistent with a classification of likely benign in the context of Li-Fraumeni syndrome. However, loss of heterozygosity was seen in the tumor of an affected individual with breast cancer in this observed family, which provides some evidence for pathogenicity with regard to the individual's breast cancer. We cannot rule out the possibility that this variant may cause some increased risk for breast cancer or other cancers. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot provided1not provided

Last Updated: Apr 12, 2021

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