rs758194998

Variant names:

• chr17-7673226-G-A
• rs758194998
• ENST00000455263.6:c.1034C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-7673226-G-A
• chr17-7673226-G-C
• chr17-7673226-G-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001126113.3(TP53):​c.1034C>T​(p.Ser345Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000183 in 1,204,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S345S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: TP53 NM_001126113.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.882
• Publications: 17 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12897661).
• BP6: Variant 17-7673226-G-A is Benign according to our data. Variant chr17-7673226-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 492648.
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126113.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	NM_000546.6	MANE Select	c.993+309C>T		intron	N/A	NP_000537.3
	TP53	NM_001126113.3		c.1034C>T	p.Ser345Leu	missense	Exon 10 of 12	NP_001119585.1	P04637-3
	TP53	NM_001276695.3		c.917C>T	p.Ser306Leu	missense	Exon 10 of 12	NP_001263624.1	P04637-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000455263.6	TSL:1	c.1034C>T	p.Ser345Leu	missense	Exon 10 of 12	ENSP00000398846.2	P04637-3
	TP53	ENST00000610538.4	TSL:1	c.917C>T	p.Ser306Leu	missense	Exon 10 of 12	ENSP00000480868.1	P04637-6
	TP53	ENST00000504290.5	TSL:1	c.638C>T	p.Ser213Leu	missense	Exon 6 of 8	ENSP00000484409.1	P04637-9

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151436 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000183 AC: 3 AN: 163558 AF XY: 0.0000346

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000399

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000157

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000199 AC: 21 AN: 1052776 Hom.: 0 Cov.: 14 AF XY: 0.0000187 AC XY: 10 AN XY: 534610

African (AFR) AF: 0.00 AC: 0 AN: 24854

American (AMR) AF: 0.0000282 AC: 1 AN: 35462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22998

East Asian (EAS) AF: 0.00 AC: 0 AN: 35032

South Asian (SAS) AF: 0.0000276 AC: 2 AN: 72506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5036

European-Non Finnish (NFE) AF: 0.0000197 AC: 15 AN: 760514

Other (OTH) AF: 0.0000644 AC: 3 AN: 46610

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151436 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73898

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41174

American (AMR) AF: 0.00 AC: 0 AN: 15182

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000226 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000863 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.0030	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	9.2
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0068	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.13	T
MetaSVM	Pathogenic	0.86	D
PhyloP100		0.88
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.26
MutPred		0.29		Loss of disorder (P = 0.0033)
MVP		0.81
ClinPred		0.094	T
GERP RS		0.89
PromoterAI		-0.011	Neutral

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: rs758194998; hg19: chr17-7576544; COSMIC: COSV53014174; COSMIC: COSV53014174;