NM_001048174.2(MUTYH):c.54_57dup (p.Glu20fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 31, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001177178.4

Allele description [Variation Report for NM_001048174.2(MUTYH):c.54_57dup (p.Glu20fs)]

NM_001048174.2(MUTYH):c.54_57dup (p.Glu20fs)

Gene:

MUTYH:mutY DNA glycosylase [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

1p34.1

Genomic location:

Preferred name:

NM_001048174.2(MUTYH):c.54_57dup (p.Glu20fs)

HGVS:

NC_000001.11:g.45334452GCTG[3]
NC_000001.11:g.45334452_45334455GCTG[3]
NG_008189.1:g.11015CCAG[3]
NM_001048171.2:c.54_57dup
NM_001048172.2:c.54_57dup
NM_001048173.2:c.54_57dup
NM_001048174.2:c.54_57dupMANE SELECT
NM_001128425.2:c.96_99dup
NM_001293190.2:c.96_99dup
NM_001293191.2:c.54_57dup
NM_001293192.2:c.-163CCAG[3]
NM_001293195.2:c.54_57dup
NM_001293196.2:c.-163CCAG[3]
NM_001350650.2:c.-222CCAG[3]
NM_001350651.2:c.-158CCAG[3]
NM_012222.3:c.96_99dup
NP_001041636.2:p.Glu20fs
NP_001041637.1:p.Glu20fs
NP_001041638.1:p.Glu20fs
NP_001041639.1:p.Glu20fs
NP_001121897.1:p.Glu34fs
NP_001280119.1:p.Glu34fs
NP_001280120.1:p.Glu20fs
NP_001280124.1:p.Glu20fs
NP_036354.1:p.Glu34fs
LRG_220t1:c.96_99dup
LRG_220:g.11015CCAG[3]
NC_000001.10:g.45800124GCTG[3]
NM_001128425.1:c.96_99dup
NM_001128425.1:c.96_99dupCCAG
NR_146882.2:n.278CCAG[3]
NR_146883.2:n.201CCAG[3]

Protein change:

E20fs

Links:

dbSNP: rs1645571595

NCBI 1000 Genomes Browser:

rs1645571595

Molecular consequence:

NM_001293192.2:c.-163CCAG[3] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001293196.2:c.-163CCAG[3] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350650.2:c.-222CCAG[3] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350651.2:c.-158CCAG[3] - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001048171.2:c.54_57dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001048172.2:c.54_57dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001048173.2:c.54_57dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001048174.2:c.54_57dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001128425.2:c.96_99dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001293190.2:c.96_99dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001293191.2:c.54_57dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001293195.2:c.54_57dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_012222.3:c.96_99dup - frameshift variant - [Sequence Ontology: SO:0001589]
NR_146882.2:n.278CCAG[3] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.201CCAG[3] - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Homo sapiens sema domain, immunoglobulin domain (Ig), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 4D, mRNA (cDNA clone MGC:57659 IMAGE:5551182), complete cds
gi|32493364|gb|BC054500.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001341350	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 27, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005038135	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jan 31, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001341350

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 27, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005038135

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jan 31, 2024)

germline

clinical testing

Citation Link

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001341350.2

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

Description

This variant inserts 4 nucleotides in exon 2 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is 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

From Ambry Genetics, SCV005038135.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The c.96_99dupCCAG variant, located in coding exon 2 of the MUTYH gene, results from a duplication of CCAG at nucleotide position 96, causing a translational frameshift with a predicted alternate stop codon (p.E34Pfs*9). The predicted stop codon occurs in the 5’ end of theMUTYH gene. Premature termination codons in the 5’ end of a gene have been reported to escape nonsense-mediated mRNAdecay and/or lead to re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). Direct evidence for this alteration is unavailable, however premature termination codons are typically deleterious in nature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be 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: May 7, 2024

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