chr8-127738428-C-A

Variant names:

• chr8-127738428-C-A
• rs767700277
• NM_002467.6:c.211C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_002467.6(MYC):​c.211C>A​(p.Leu71Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYC NM_002467.6 missense
• Clinical Significance: Other O:1
• Conservation: PhyloP100: 4.01
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_002467.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.2227 (below the threshold of 3.09). Trascript score misZ: 1.518 (below the threshold of 3.09). GenCC associations: The gene is linked to Burkitt lymphoma.
• BP4: Computational evidence support a benign effect (REVEL=0.289).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002467.6. 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
	MYC	NM_002467.6	MANE Select	c.211C>A	p.Leu71Met	missense	Exon 2 of 3	NP_002458.2	P01106-2
	MYC	NM_001354870.1		c.208C>A	p.Leu70Met	missense	Exon 2 of 3	NP_001341799.1	P01106-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYC	ENST00000621592.8	TSL:1 MANE Select	c.211C>A	p.Leu71Met	missense	Exon 2 of 3	ENSP00000478887.2	P01106-2
	MYC	ENST00000524013.2	TSL:1	c.208C>A	p.Leu70Met	missense	Exon 2 of 3	ENSP00000430235.2	P01106-3
	MYC	ENST00000377970.6	TSL:1	c.166C>A	p.Leu56Met	missense	Exon 2 of 3	ENSP00000367207.3	P01106-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Other

Revision:

Pathogenic	VUS	Benign	Condition
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.083	D
PhyloP100		4.0
ClinPred		0.98	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.52
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs767700277; hg19: chr8-128750674; COSMIC: COSV104388218; COSMIC: COSV104388218;