17-7673790-C-T

Position:

• chr17-7673790-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000546.6(TP53):​c.830G>A​(p.Cys277Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2 O:1
• Conservation: PhyloP100: 6.08

Genes affected

TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a region_of_interest Interaction with DNA (size 7) in uniprot entity P53_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 17-7673790-C-T is Pathogenic according to our data. Variant chr17-7673790-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 185722.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, not_provided=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.830G>A	p.Cys277Tyr	missense_variant	8/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.830G>A	p.Cys277Tyr	missense_variant	8/11	1	NM_000546.6	ENSP00000269305	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461848 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000983 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	TP53: PS3:Moderate, PM2:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2023	Published functional studies demonstrate a damaging effect: loss of transcriptional activation activity with a dominant-negative effect, reduced apoptotic activity (Epstein et al., 1998; Di Como et al., 1998; Kato et al., 2003; Pospisilova et al., 2004; Dearth et al., 2007; Monti et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with anaplastic thyroid cancer (Garg et al., 2015); This variant is associated with the following publications: (PMID: 10519380, 12759621, 9627118, 27311873, 11406645, 31414729, 30840781, 19336573, 24113472, 22915647, 9482117, 8378080, 21343334, 21232794, 21472523, 19681600, 21197471, 9572492, 16861262, 8633021, 9546439, 23117049, 19671856, 26723900, 11238924, 15192123, 17606709, 16818505, 29979965, 28861920, 30720243, 28884749, 28866070, 27813088, 29922827, 30224644, 32980694, 15510160, 12826609, 25365311, 35050731) -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Uncertain significance and reported on 12-26-2018 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Li-Fraumeni syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 12, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 277 of the TP53 protein (p.Cys277Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with anaplastic thyroid cancer, osteosarcoma, and/or prostate cancer (PMID: 12759621, 19671856, 25365311, 27328919; Invitae). ClinVar contains an entry for this variant (Variation ID: 185722). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 29979965). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Adrenocortical carcinoma, hereditary Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 30, 2021

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2023

The p.C277Y variant (also known as c.830G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 830. The cysteine at codon 277 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been reported in the germline of a child diagnosed with an osteosarcoma at age 14 (Patiño-García A et al. J Pediatr Hematol Oncol. 2003 May;25:362-7). This alteration has also been associated with loss-of-heterozygosity (LOH) in tumor DNA from an individual diagnosed with osteosarcoma at age 22 and is a common somatic mutation detected in Ewing's sarcoma (Patiño-García A et al. Clin. Cancer Res. 2009 Aug;15(16):5082-91; Pospísilová S et al. Mol. Cancer Res. 2004 May; 2(5):296-304). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration is located in the highly conserved DNA binding domain at a residue that has been shown to be directly involved in DNA contact (Martin AC et al. Hum. Mutat. 2002 Feb; 19(2):149-64). 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 was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The TP53 p.Cys277Tyr variant was identified in 1 of 14,718 proband chromosomes (frequency: 0.00007) from individuals with anaplastic thyroid and unspecified cancer and was present in 1 of 22,482 control chromosomes (frequency: 0.00004) from healthy individuals (Momozawa 2018, Monti 2007). The variant was identified in dbSNP (rs763098116) as “with likely pathogenic, uncertain significance allele”, in ClinVar (classified as likely pathogenic by GeneDx and Ambry Genetics and uncertain significance by Invitae) and LOVD 3.0 (observed 1x). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 1 of 117,922 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 65,130 chromosomes (freq: 0.00002), but not in the African, East Asian, Finnish, Latino, Other, and South Asian populations. In a number of yeast-based assays, the variant altered the transactivation activity of p53 exhibiting a dominant negative effect over wild type (Epstein 1998, Flaman 1998, Gagnebin 1998, Di Como 1998). Conversely, in vitro expression of the variant retained p53-mediated apoptosis plus binding and activation of several downstream targets (Pospisilova 2004, Ferrone 2006). Overall, these studies have led to inconclusive findings about the functional effects of the variant. The p.Cys277 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.2	.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-10	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.
Vest4		0.94
MutPred		0.92		Loss of disorder (P = 0.0556);.;.;.;.;.;.;.;Loss of disorder (P = 0.0556);.;Loss of disorder (P = 0.0556);Loss of disorder (P = 0.0556);Loss of disorder (P = 0.0556);.;.;Loss of disorder (P = 0.0556);.;.;.;
MVP		0.99
MPC		0.46
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs763098116; hg19: chr17-7577108; COSMIC: COSV52826087; COSMIC: COSV52826087;