8-127738434-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP5_Moderate

The NM_002467.6(MYC):c.217A>G(p.Thr73Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). 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: not found (cov: 33)
• Consequence: MYC NM_002467.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• 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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-127738435-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376300.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant 8-127738434-A-G is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYC	NM_002467.6	c.217A>G	p.Thr73Ala	missense_variant	2/3	ENST00000621592.8
MYC	NM_001354870.1	c.214A>G	p.Thr72Ala	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYC	ENST00000621592.8	c.217A>G	p.Thr73Ala	missense_variant	2/3	1	NM_002467.6	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000465 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

MYC: PM1:Strong, PM2, PS3:Moderate, PS4:Moderate -

Acute myeloid leukemia Other:1

-, no assertion criteria provided

clinical testing

Molecular Diagnostics Laboratory, Fox Chase Cancer Center - Temple Health

Jan 24, 2024

This variant was detected in a relapsed acute myeloid leukemia patient as a somatic mutation accompanied by a AKAP9::PDGFRA translocation. It is predicted Pathogenic Supporting by FATHMM-MKL, is reported in lymphoid neoplasms in COSMIC (COSV52367574) and cBioPortal, and has not been observed in the general population. Also known as p.Thr58Ala in Ensembl, this variant form of MYC is not subject to a phosphorylation signal that targets MYC for degradation and is an activating oncogenic lesion. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.11	T;T;T;T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.6	D;D;.;.;D;.
REVEL	Uncertain	0.30
Sift	Benign	0.037	D;D;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.99	.;.;.;D;.;.
Vest4		0.70
MutPred		0.58		Loss of glycosylation at T58 (P = 0.021);.;.;Loss of glycosylation at T58 (P = 0.021);.;.;
MVP		0.71
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.61
gMVP		0.70

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: COSV52367574; COSMIC: COSV52367574;