17-7676224-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1 BP4_Moderate BP6_Very_Strong

The NM_000546.6(TP53):c.145G>C(p.Asp49His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D49N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Likely benign reviewed by expert panel U:9 B:2
• Conservation: PhyloP100: 0.360

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 Benign. Variant got -8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 16 uncertain in NM_000546.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.1856136).
• BP6: Variant 17-7676224-C-G is Benign according to our data. Variant chr17-7676224-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 135948.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.145G>C	p.Asp49His	missense_variant	4/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.145G>C	p.Asp49His	missense_variant	4/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152108 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251366 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461880 Hom.: 0 Cov.: 57 AF XY: 0.0000316 AC XY: 23 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00108

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152108 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74300

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000384

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:9 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Li-Fraumeni syndrome 1 Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 07, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 11, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Likely benign, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Jan 10, 2022	This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor). In summary, TP53 c.125G>C (p.D49H) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BP4, BS2_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Li-Fraumeni syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 49 of the TP53 protein (p.Asp49His). This variant is present in population databases (rs587780728, gnomAD 0.01%). This missense change has been observed in individual(s) with sarcoma, lymphoma, pancreatic cancer, prostate cancer, biliary tract cancer, and/or breast cancer (PMID: 27545002, 28902083, 29667044, 30287823, 34863587). ClinVar contains an entry for this variant (Variation ID: 135948). 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: 9207066, 12826609, 12901974, 15489903, 30224644). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 31, 2023	This missense variant replaces aspartic acid with histidine at codon 49 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported the variant protein to activate VEGF expression and increased growth support in leukemic cells and p53-null cell line (PMID: 12901974). However, yeast studies have reported the variant protein to be non-functional in transcription activation (PMID: 12826609 and IARC database). This variant in combination with p.D48H in TP53 peptide and full-length protein has also been reported to have lost RPA binding and the suppression of homologous recombination (PMID: 9207066, 15489903). This variant has been reported in two individuals diagnosed with Li-Fraumani syndrome (LFS), and one of which has a second TP53 covariant (PMID: 28902083, 27545002). This variant has also been reported in five individuals with cancer history but do not meet the criteria for LFS or Li-Fraumani-like syndrome (PMID: 27545002), in three individuals affected with sarcoma, and in one healthy control (PMID: 1565143). This variant has been identified in 1/251366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has conflicting reports on functional impact and has been observed in affected individuals as well as in the general population. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 17, 2023	The p.D49H variant (also known as c.145G>C), located in coding exon 3 of the TP53 gene, results from a G to C substitution at nucleotide position 145. The aspartic acid at codon 49 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in six patients from a cohort of 1685 Japanese adult patients with various cancers (Yamaguchi K et al. Biomed. Res., 2016;37:259-64). Of these cases, only one of the six met clinical criteria for Li-Fraumeni-Like syndrome (LFL), but this individual was also noted to carry the TP53 p.A159D germline alteration. Further, this alteration has been identified in a 15 year old boy with lymphocyte-predominant Hodgkin lymphoma, and was also identified in his sister who has a history of rhabdomyosarcoma at the age of 1.5 years (Yamazaki F et al. J. Pediatr. Hematol. Oncol. 2017 Sep). This alteration was observed in with an allele frequency of 0.00511 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00445 in 11,241 female controls of Japanese ancestry. In addition, it was observed with an allele frequency of 0.0189 in 53 male breast cancer patients and was observed with an allele frequency of 0.0054 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). In another study, this variant was identified in 69/12,434 unselected Japanese colorectal cancer patients and in 117/23,588 controls (Fujita M et al. Clin Gastroenterol Hepatol, 2022 Sep;20:2132-2141.e9). This alteration was shown to have a loss of transactivation capacity in yeast-based functional studies (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9), and increase VEGF expression in mammalian cells (Narendran A et al. Exp. Hematol. 2003 Aug;31:693-701). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is not well conserved on limited sequence alignment. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 15, 2022	This missense variant replaces aspartic acid with histidine at codon 49 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported the variant protein to activate VEGF expression and increased growth support in leukemic cells and p53-null cell line (PMID: 12901974). However, yeast studies have reported the variant protein to be non-functional in transcription activation (PMID: 12826609 and IARC database). This variant in combination with p.D48H in TP53 peptide and full-length protein has also been reported to have lost RPA binding and the suppression of homologous recombination (PMID: 9207066, 15489903). This variant has been reported in two individuals diagnosed with Li-Fraumani syndrome (LFS), and one of which has a second TP53 covariant (PMID: 28902083, 27545002). This variant has also been reported in five individuals with cancer history but do not meet the criteria for LFS or Li-Fraumani-like syndrome (PMID: 27545002), in three individuals affected with sarcoma, and in one healthy control (PMID: 1565143). This variant has been identified in 1/251366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has conflicting reports on functional impact and has been observed in affected individuals as well as in the general population. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 14, 2019	Variant summary: TP53 c.145G>C (p.Asp49His) results in a non-conservative amino acid change located in the transactivation domain 2 of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246194 control chromosomes (gnomad). This variant has been reported in the literature in individuals affected with Li-Fraumeni Syndrome and other cancers (Yamaguchi_2016, Yamazaki_2018, Ohmoto_2018). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Narendran_2003). The transfection experiment demonstrated the ability of p.Asp49His to increase the expression of VEGF. However, the association between this effect to Li-Fraumeni Syndrome is not clear. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	8.2
Dann	Uncertain	0.98
DEOGEN2	Benign	0.026	T;T;.;D;.;.;.;.;.;.;D;.;.;T;T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.90	D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.86	D
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.34	N;N;.;N;.;.;N;N;.;.;N;.;.;N;.;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D;D;.;D;.;.;D;D;.;.;D;.;.;D;.;D
Sift4G	Uncertain	0.025	D;D;D;D;D;D;D;D;D;D;D;D;D;.;T;.
Polyphen		1.0	D;.;.;D;.;D;D;D;.;.;D;.;.;D;.;.
Vest4		0.37
MutPred		0.18		Loss of phosphorylation at S46 (P = 0.1138);Loss of phosphorylation at S46 (P = 0.1138);.;Loss of phosphorylation at S46 (P = 0.1138);.;Loss of phosphorylation at S46 (P = 0.1138);Loss of phosphorylation at S46 (P = 0.1138);Loss of phosphorylation at S46 (P = 0.1138);.;.;Loss of phosphorylation at S46 (P = 0.1138);.;Loss of phosphorylation at S46 (P = 0.1138);Loss of phosphorylation at S46 (P = 0.1138);Loss of phosphorylation at S46 (P = 0.1138);Loss of phosphorylation at S46 (P = 0.1138);
MVP		0.95
MPC		1.5
ClinPred		0.64	D
GERP RS		0.46
Varity_R		0.49
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587780728; hg19: chr17-7579542; COSMIC: COSV52732514; COSMIC: COSV52732514;