chr17-7669662-T-G

Position:

• chr17-7669662-T-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The ENST00000269305.9(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. 13/21 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 Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TP53 ENST00000269305.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.464

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 Likely_benign. Variant got -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 id is 975959.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.1129A>C	p.Thr377Pro	missense_variant	11/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.1129A>C	p.Thr377Pro	missense_variant	11/11	1	NM_000546.6	ENSP00000269305	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 8 AN: 150890 Hom.: 0 Cov.: 32 FAILED QC

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

GnomAD3 exomes AF: 0.000287 AC: 71 AN: 247380 Hom.: 0 AF XY: 0.000231 AC XY: 31 AN XY: 133994

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 SAS exome AF: 0.000229

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

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000698

Gnomad4 FIN exome AF: 0.000230

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000166

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000659

Gnomad4 ASJ AF: 0.000290

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000593

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000104 Hom.: 0

ExAC AF: 0.000725 AC: 88

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Li-Fraumeni syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Mar 06, 2018

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Apr 12, 2024

Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).For TP53, we used the output of the Naïve Bayes classifier that synthesized data from four different TP53 MAVEs in Fayer et al. (2021) (PMID: 34793697). If the classifier predicted a variant to be "Functionally abnormal," the variant was assigned PS3 evidence and no BS3 evidence. If a variant was predicted to be "Functionally normal," BS3_moderate evidence was used with no PS3 evidence. This variant GRCh37:17:7572980:T>G was assigned evidence codes ['BS3_Moderate', 'BP4'] and an overall classification of Likely Benign -

Computational scores

Source: dbNSFP v4.3

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;.;T;.;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.60	T;T;.;.;.;T;T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	1.2	.;.;.;L;.;L;.;.
MutationTaster	Benign	0.88	D;D;D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	2.8	.;.;.;N;.;N;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.44	.;.;.;T;.;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.0020	.;.;.;B;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs774269719; hg19: chr17-7572980; COSMIC: COSV52716766; COSMIC: COSV52716766;