NM_001276270.2(MBD4):c.541C>T (p.Arg181Ter) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 16, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003665855.2

Allele description [Variation Report for NM_001276270.2(MBD4):c.541C>T (p.Arg181Ter)]

NM_001276270.2(MBD4):c.541C>T (p.Arg181Ter)

Gene:

MBD4:methyl-CpG binding domain 4, DNA glycosylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q21.3

Genomic location:

Preferred name:

NM_001276270.2(MBD4):c.541C>T (p.Arg181Ter)

HGVS:

NC_000003.12:g.129437103G>A
NG_023392.1:g.1979G>A
NG_033106.1:g.8077C>T
NM_001276270.2:c.541C>TMANE SELECT
NM_001276271.2:c.541C>T
NM_001276272.2:c.541C>T
NM_001276273.2:c.247+705C>T
NM_003925.3:c.541C>T
NP_001263199.1:p.Arg181Ter
NP_001263200.1:p.Arg181Ter
NP_001263201.1:p.Arg181Ter
NP_003916.1:p.Arg181Ter
NC_000003.11:g.129155946G>A

Protein change:

R181*

Molecular consequence:

NM_001276273.2:c.247+705C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001276270.2:c.541C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001276271.2:c.541C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001276272.2:c.541C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_003925.3:c.541C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004378113	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 16, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30049810, 35460607, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004378113

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 16, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML.

Sanders MA, Chew E, Flensburg C, Zeilemaker A, Miller SE, Al Hinai AS, Bajel A, Luiken B, Rijken M, Mclennan T, Hoogenboezem RM, Kavelaars FG, Fröhling S, Blewitt ME, Bindels EM, Alexander WS, Löwenberg B, Roberts AW, Valk PJM, Majewski IJ.

Blood. 2018 Oct 4;132(14):1526-1534. doi: 10.1182/blood-2018-05-852566. Epub 2018 Jul 26. Erratum in: Blood. 2023 Feb 16;141(7):808-809. doi: 10.1182/blood.2022018609.

PubMed [citation]

PMID:: 30049810
PMCID:: PMC6172562

Germline MBD4 deficiency causes a multi-tumor predisposition syndrome.

Palles C, West HD, Chew E, Galavotti S, Flensburg C, Grolleman JE, Jansen EAM, Curley H, Chegwidden L, Arbe-Barnes EH, Lander N, Truscott R, Pagan J, Bajel A, Sherwood K, Martin L, Thomas H, Georgiou D, Fostira F, Goldberg Y, Adams DJ, van der Biezen SAM, et al.

Am J Hum Genet. 2022 May 5;109(5):953-960. doi: 10.1016/j.ajhg.2022.03.018. Epub 2022 Apr 22.

PubMed [citation]

PMID:: 35460607
PMCID:: PMC9118112

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004378113.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Arg181*) in the MBD4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MBD4 are known to be pathogenic (PMID: 30049810, 35460607). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MBD4-related conditions. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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