Genetic Variant MGMT:p.Thr38Met (chr10-129536365-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002412.5(MGMT):c.113C>T(p.Thr38Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,612,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

MGMT
NM_002412.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.699

Publications

0 publications found

Variant links:

Genes affected

MGMT (HGNC:7059): (O-6-methylguanine-DNA methyltransferase) Alkylating agents are potent carcinogens that can result in cell death, mutation and cancer. The protein encoded by this gene is a DNA repair protein that is involved in cellular defense against mutagenesis and toxicity from alkylating agents. The protein catalyzes transfer of methyl groups from O(6)-alkylguanine and other methylated moieties of the DNA to its own molecule, which repairs the toxic lesions. Methylation of the genes promoter has been associated with several cancer types, including colorectal cancer, lung cancer, lymphoma and glioblastoma. [provided by RefSeq, Sep 2015]

MGMT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15237924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGMT	NM_002412.5 link	c.113C>T	p.Thr38Met	missense_variant	Exon 2 of 5	ENST00000651593.1	NP_002403.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MGMT	ENST00000651593.1 link	c.113C>T	p.Thr38Met	missense_variant	Exon 2 of 5		NM_002412.5	ENSP00000498729.1	P16455
MGMT	ENST00000306010.8 link	c.206C>T	p.Thr69Met	missense_variant	Exon 2 of 5	1		ENSP00000302111.7	B4DEE8
MGMT	ENST00000482547.1 link	n.160C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2
MGMT	ENST00000482653.1 link	n.193C>T		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000240

AC:

AN:

250132

AF XY:

0.0000296

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000541

AC:

AN:

1460806

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

726738

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33378

American (AMR)

AF:

0.00

AC:

AN:

44294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86116

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000585

AC:

AN:

1111736

Other (OTH)

AF:

0.0000829

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.582

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000772

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.206C>T (p.T69M) alteration is located in exon 2 (coding exon 2) of the MGMT gene. This alteration results from a C to T substitution at nucleotide position 206, causing the threonine (T) at amino acid position 69 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.43

M_CAP

Benign

0.016

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.1

PhyloP100

-0.70

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.7

REVEL

Benign

0.034

Sift

Benign

0.050

Sift4G

Benign

0.077

Vest4

0.25

MutPred

0.39

Loss of phosphorylation at T69 (P = 0.0773);

MVP

0.20

MPC

0.13

ClinPred

0.24

GERP RS

-3.1

gMVP

0.37

Mutation Taster

=82/18

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr10-129536365-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over