8-127738447-C-T

Position:

• chr8-127738447-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_002467.6(MYC):​c.230C>T​(p.Ser77Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYC NM_002467.6 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.88

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.

• PM1: In a mutagenesis_site Impairs interaction with FBXW7 and subsequent degradation by the proteasome. Impaired inhibition of Ras-induced senescence. Abolishes phosphorylation by DYRK2, and subsequent phosphorylation by GSK3B at Thr-73. (size 0) in uniprot entity MYC_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762
• PP5: Variant 8-127738447-C-T is Pathogenic according to our data. Variant chr8-127738447-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376301.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYC	NM_002467.6	c.230C>T	p.Ser77Phe	missense_variant	2/3	ENST00000621592.8
MYC	NM_001354870.1	c.227C>T	p.Ser76Phe	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYC	ENST00000621592.8	c.230C>T	p.Ser77Phe	missense_variant	2/3	1	NM_002467.6	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	32
DANN	Benign	0.97
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.57	T
MutationTaster	Benign	1.0	D
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.67
MutPred		0.10		Gain of phosphorylation at P51 (P = 0.0079);
MVP		0.87
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

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: rs1057519850; hg19: chr8-128750693; COSMIC: COSV52371924; COSMIC: COSV52371924;