rs750664148

chr8-127738434-A-Cchr8-127738434-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM5 PP3 PP5 BP4

The NM_002467.6(MYC):c.217A>C(p.Thr73Pro) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T73I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYC NM_002467.6 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:5
• Conservation: PhyloP100: 6.08

Genes affected

MYC (HGNC:7553): (MYC proto-oncogene, bHLH transcription factor) This gene is a proto-oncogene and encodes a nuclear phosphoprotein that plays a role in cell cycle progression, apoptosis and cellular transformation. The encoded protein forms a heterodimer with the related transcription factor MAX. This complex binds to the E box DNA consensus sequence and regulates the transcription of specific target genes. Amplification of this gene is frequently observed in numerous human cancers. Translocations involving this gene are associated with Burkitt lymphoma and multiple myeloma in human patients. There is evidence to show that translation initiates both from an upstream, in-frame non-AUG (CUG) and a downstream AUG start site, resulting in the production of two isoforms with distinct N-termini. [provided by RefSeq, Aug 2017]

CASC11 (HGNC:48939): (cancer susceptibility 11)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-127738434-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2658815.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, Cadd, Eigen, FATHMM_MKL, MutationAssessor, PROVEAN [when BayesDel_noAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 8-127738434-A-C is Pathogenic according to our data. Variant chr8-127738434-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376458.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.014192492).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYC	NM_002467.6	c.217A>C	p.Thr73Pro	missense_variant	2/3	ENST00000621592.8
MYC	NM_001354870.1	c.214A>C	p.Thr72Pro	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYC	ENST00000621592.8	c.217A>C	p.Thr73Pro	missense_variant	2/3	1	NM_002467.6	A2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 33 AN: 150740 Hom.: 0 Cov.: 33 FAILED QC

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000400

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00141 AC: 2031 AN: 1435484 Hom.: 0 Cov.: 32 AF XY: 0.00160 AC XY: 1139 AN XY: 712016

Gnomad4 AFR exome AF: 0.000303

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00233

Gnomad4 EAS exome AF: 0.000804

Gnomad4 SAS exome AF: 0.000287

Gnomad4 FIN exome AF: 0.00238

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000219 AC: 33 AN: 150740 Hom.: 0 Cov.: 33 AF XY: 0.000299 AC XY: 22 AN XY: 73572

Gnomad4 AFR AF: 0.0000488

Gnomad4 AMR AF: 0.000198

Gnomad4 ASJ AF: 0.000290

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000400

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000140 Hom.: 0

ExAC AF: 0.0116 AC: 1409

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: no assertion criteria provided

Submissions by phenotype

Neuroblastoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Carcinoma of esophagus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lung adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Non-Hodgkin lymphoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant melanoma of skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.091	T;T;T;T;T;T
MetaRNN	Benign	0.014	T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.6	D;D;.;.;D;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.029	D;D;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	.;.;.;D;.;.
Vest4		0.39
ClinPred		0.043	T
GERP RS		4.8
Varity_R		0.83
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs750664148; hg19: chr8-128750680; COSMIC: COSV52369643; COSMIC: COSV52369643;