17-7673319-T-A

Variant names:

• chr17-7673319-T-A
• rs761303879
• ENST00000420246.6:c.1014A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001126114.3(TP53):​c.1014A>T​(p.Lys338Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_001126114.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15533242).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126114.3. 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+216A>T		intron	N/A	NP_000537.3
	TP53	NM_001126114.3		c.1014A>T	p.Lys338Asn	missense	Exon 10 of 12	NP_001119586.1	P04637-2
	TP53	NM_001407268.1		c.1014A>T	p.Lys338Asn	missense	Exon 10 of 12	NP_001394197.1	P04637-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000420246.6	TSL:1	c.1014A>T	p.Lys338Asn	missense	Exon 10 of 12	ENSP00000391127.2	P04637-2
	TP53	ENST00000622645.4	TSL:1	c.897A>T	p.Lys299Asn	missense	Exon 10 of 12	ENSP00000482222.1	P04637-5
	TP53	ENST00000510385.5	TSL:1	c.618A>T	p.Lys206Asn	missense	Exon 6 of 8	ENSP00000478499.1	P04637-8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.40	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.16	T
MetaSVM	Pathogenic	0.86	D
PhyloP100		1.1
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.32
Sift	Benign	0.041	D
Sift4G	Uncertain	0.042	D
Polyphen		0.63	P
Vest4		0.20
MutPred		0.12		Loss of ubiquitination at K338 (P = 0.0023)
MVP		0.86
ClinPred		0.17	T
GERP RS		2.6
PromoterAI		0.0010	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: rs761303879; hg19: chr17-7576637;