NM_000546.6:c.673-37C>T

Variant names:

• chr17-7674327-G-A
• rs374907737
• NM_000546.6:c.673-37C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000546.6(TP53):​c.673-37C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,326,402 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: TP53 NM_000546.6 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.389
• Publications: 2 publications found

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]

TP53 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• Li-Fraumeni syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• Li-Fraumeni syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• adrenocortical carcinoma, hereditary

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• bone marrow failure syndrome 5

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• colorectal cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• choroid plexus carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-7674327-G-A is Benign according to our data. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964. Variant chr17-7674327-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 371964.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000174 (204/1174616) while in subpopulation SAS AF = 0.00102 (82/80568). AF 95% confidence interval is 0.00084. There are 0 homozygotes in GnomAdExome4. There are 129 alleles in the male GnomAdExome4 subpopulation. Median coverage is 17. This position passed quality control check.
• BS2: High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.673-37C>T		intron_variant	Intron 6 of 10	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.673-37C>T		intron_variant	Intron 6 of 10	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 151684 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000236 AC: 59 AN: 250068 AF XY: 0.000325

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000174 AC: 204 AN: 1174616 Hom.: 0 Cov.: 17 AF XY: 0.000216 AC XY: 129 AN XY: 597790

African (AFR) AF: 0.0000718 AC: 2 AN: 27868

American (AMR) AF: 0.000180 AC: 8 AN: 44346

Ashkenazi Jewish (ASJ) AF: 0.0000410 AC: 1 AN: 24400

East Asian (EAS) AF: 0.00 AC: 0 AN: 38334

South Asian (SAS) AF: 0.00102 AC: 82 AN: 80568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52970

Middle Eastern (MID) AF: 0.000197 AC: 1 AN: 5078

European-Non Finnish (NFE) AF: 0.000123 AC: 105 AN: 850200

Other (OTH) AF: 0.0000983 AC: 5 AN: 50852

GnomAD4 genome AF: 0.000105 AC: 16 AN: 151786 Hom.: 0 Cov.: 30 AF XY: 0.000108 AC XY: 8 AN XY: 74150

African (AFR) AF: 0.0000725 AC: 3 AN: 41394

American (AMR) AF: 0.0000656 AC: 1 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67934

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.0000907

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Jul 17, 2015

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.673-37C>T intronic alteration consists of a C to T substitution 37 nucleotides before coding exon 6 in the TP53 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Li-Fraumeni syndrome 1 Benign:2

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 13, 2016

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Sep 28, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TP53-related disorder Benign:1

Aug 31, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.1
DANN	Benign	0.78
PhyloP100		0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs374907737; hg19: chr17-7577645;