17-7669662-T-G

Variant names:

• chr17-7669662-T-G
• rs774269719
• NM_000546.6:c.1129A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000546.6(TP53):​c.1129A>C​(p.Thr377Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T377I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.464
• Publications: 32 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010908842).
• BP6: Variant 17-7669662-T-G is Benign according to our data. Variant chr17-7669662-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 975959.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000546.6. 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.1129A>C	p.Thr377Pro	missense	Exon 11 of 11	NP_000537.3
	TP53	NM_001126112.3		c.1129A>C	p.Thr377Pro	missense	Exon 11 of 11	NP_001119584.1
	TP53	NM_001407262.1		c.1129A>C	p.Thr377Pro	missense	Exon 12 of 12	NP_001394191.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.1129A>C	p.Thr377Pro	missense	Exon 11 of 11	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.1129A>C	p.Thr377Pro	missense	Exon 11 of 11	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.1012A>C	p.Thr338Pro	missense	Exon 10 of 10	ENSP00000478219.1

Frequencies

GnomAD3 genomes AF: 0.0000530 AC: 8 AN: 150890 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000660

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000593

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000287 AC: 71 AN: 247380 AF XY: 0.000231

Gnomad AFR exome AF: 0.000496

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000399

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000454

Gnomad NFE exome AF: 0.000366

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000672 AC: 98 AN: 1458674 Hom.: 0 Cov.: 31 AF XY: 0.0000689 AC XY: 50 AN XY: 725644

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

African (AFR) AF: 0.0000897 AC: 3 AN: 33438

American (AMR) AF: 0.0000224 AC: 1 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000698 AC: 6 AN: 86020

European-Finnish (FIN) AF: 0.000230 AC: 12 AN: 52090

Middle Eastern (MID) AF: 0.0107 AC: 51 AN: 4766

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111596

Other (OTH) AF: 0.000166 AC: 10 AN: 60276

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000464 AC: 7 AN: 150988 Hom.: 0 Cov.: 32 AF XY: 0.0000678 AC XY: 5 AN XY: 73712

⚠️ 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: 41246

American (AMR) AF: 0.0000659 AC: 1 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.000290 AC: 1 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5088

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000593 AC: 4 AN: 67428

Other (OTH) AF: 0.00 AC: 0 AN: 2098

⚠️ 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: 0.0000412 Hom.: 0

ExAC AF: 0.000725 AC: 88

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	Li-Fraumeni syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	1.2	L
PhyloP100		0.46
PrimateAI	Benign	0.37	T
PROVEAN	Benign	2.8	N
REVEL	Uncertain	0.35
Sift	Benign	0.44	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.097
MVP		0.77
MPC		2.0
ClinPred		0.020	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.22
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs774269719; hg19: chr17-7572980; COSMIC: COSV52716766; COSMIC: COSV52716766;