NM_001048174.2(MUTYH):c.563G>A (p.Gly188Glu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jun 17, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000216464.7

Allele description [Variation Report for NM_001048174.2(MUTYH):c.563G>A (p.Gly188Glu)]

NM_001048174.2(MUTYH):c.563G>A (p.Gly188Glu)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

1p34.1

Genomic location:

Preferred name:

NM_001048174.2(MUTYH):c.563G>A (p.Gly188Glu)

HGVS:

NC_000001.11:g.45332617C>T
NG_008189.1:g.12854G>A
NM_001048171.2:c.563G>A
NM_001048172.2:c.566G>A
NM_001048173.2:c.563G>A
NM_001048174.2:c.563G>AMANE SELECT
NM_001128425.2:c.647G>A
NM_001293190.2:c.608G>A
NM_001293191.2:c.596G>A
NM_001293192.2:c.287G>A
NM_001293195.2:c.563G>A
NM_001293196.2:c.287G>A
NM_001350650.2:c.218G>A
NM_001350651.2:c.218G>A
NM_012222.3:c.638G>A
NP_001041636.2:p.Gly188Glu
NP_001041637.1:p.Gly189Glu
NP_001041638.1:p.Gly188Glu
NP_001041639.1:p.Gly188Glu
NP_001121897.1:p.Gly216Glu
NP_001121897.1:p.Gly216Glu
NP_001280119.1:p.Gly203Glu
NP_001280120.1:p.Gly199Glu
NP_001280121.1:p.Gly96Glu
NP_001280124.1:p.Gly188Glu
NP_001280125.1:p.Gly96Glu
NP_001337579.1:p.Gly73Glu
NP_001337580.1:p.Gly73Glu
NP_036354.1:p.Gly213Glu
LRG_220t1:c.647G>A
LRG_220:g.12854G>A
LRG_220p1:p.Gly216Glu
NC_000001.10:g.45798289C>T
NM_001128425.1:c.647G>A
NR_146882.2:n.791G>A
NR_146883.2:n.640G>A

Protein change:

G188E

Links:

dbSNP: rs768553551

NCBI 1000 Genomes Browser:

rs768553551

Molecular consequence:

NM_001048171.2:c.563G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.566G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.563G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.563G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.647G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.608G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.596G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.287G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.563G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.287G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.218G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.218G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.638G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.791G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.640G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000275359	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jun 17, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18515411, 19032956, 20618354 Citation Link,
SCV000680454	GeneID Lab - Advanced Molecular Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 7, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000275359

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jun 17, 2024)

germline

clinical testing

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

Citation Link,

SCV000680454

GeneID Lab - Advanced Molecular Diagnostics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 7, 2017)

germline

clinical testing

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

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
Latino	germline	no	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3.

Dallosso AR, Dolwani S, Jones N, Jones S, Colley J, Maynard J, Idziaszczyk S, Humphreys V, Arnold J, Donaldson A, Eccles D, Ellis A, Evans DG, Frayling IM, Hes FJ, Houlston RS, Maher ER, Nielsen M, Parry S, Tyler E, Moskvina V, Cheadle JP, et al.

Gut. 2008 Sep;57(9):1252-5. doi: 10.1136/gut.2007.145748. Epub 2008 May 30.

PubMed [citation]

PMID:: 18515411

Analysis of MUTYH genotypes and colorectal phenotypes in patients With MUTYH-associated polyposis.

Nielsen M, Joerink-van de Beld MC, Jones N, Vogt S, Tops CM, Vasen HF, Sampson JR, Aretz S, Hes FJ.

Gastroenterology. 2009 Feb;136(2):471-6. doi: 10.1053/j.gastro.2008.10.056. Epub 2008 Oct 30.

PubMed [citation]

PMID:: 19032956

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000275359.8

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

Description

The p.G216E variant (also known as c.647G>A), located in coding exon 8 of the MUTYH gene, results from a G to A substitution at nucleotide position 647. The glycine at codon 216 is replaced by glutamic acid, an amino acid with similar properties. This variant has been confirmed in trans with a MUTYH founder mutation in a patient diagnosed with three separate primary colorectal cancers at age 38 (Morak M et al. Clin Genet, 2010 Oct;78:353-63). This variant has also been detected in conjunction with a MUTYH founder mutation in an individual with multiple colorectal adenomas (Dallosso AR et al. Gut 2008 Sep; 57(9):1252-5; Vogt S et al. Gastroenterology. 2009 Dec;137(6):1976-85.e1-10) and in 1/257 patients with MUTYH-associated polyposis (Nielsen M et al. Gastroenterology, 2009 Feb;136:471-6). Additionally, this variant has been identified in at least one patient with a personal or family history of breast and/or ovarian cancer (Maxwell KN et al. Am J Hum Genet. 2016 May 5;98(5):801-17). Based on internal structural analysis using published crystal structures, p.G216E is structurally deleterious (Ambry internal data). Of note, this alteration is also designated as p.G213E in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

From GeneID Lab - Advanced Molecular Diagnostics, SCV000680454.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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