NM_001048174.2(MUTYH):c.563G>A (p.Gly188Glu) AND Familial adenomatous polyposis 2

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Feb 2, 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:: RCV000542510.14

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:: Familial adenomatous polyposis 2
Synonyms:: COLORECTAL ADENOMATOUS POLYPOSIS, AUTOSOMAL RECESSIVE; ADENOMAS, MULTIPLE COLORECTAL, AUTOSOMAL RECESSIVE; MYH-associated polyposis; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012041; MedGen: C3272841; Orphanet: 220460; OMIM: 608456

Recent activity

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endosomal integral membrane protein, putative [Trypanosoma brucei gambiense DAL9...
endosomal integral membrane protein, putative [Trypanosoma brucei gambiense DAL972]
gi|261327143|emb|CBH10119.1|

Protein
Mus musculus ORM1-like 2 (S. cerevisiae), mRNA (cDNA clone MGC:7263 IMAGE:348483...
Mus musculus ORM1-like 2 (S. cerevisiae), mRNA (cDNA clone MGC:7263 IMAGE:3484833), complete cds
gi|12805352|gb|BC002146.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000639350	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 29, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18515411, 19732775, 20618354, 28492532
SCV004198926	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 2, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004814570	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Mar 4, 2023)	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

SCV000639350

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 29, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004198926

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 2, 2024)

unknown

clinical testing

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

SCV004814570

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Mar 4, 2023)

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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	108544	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

Expanded extracolonic tumor spectrum in MUTYH-associated polyposis.

Vogt S, Jones N, Christian D, Engel C, Nielsen M, Kaufmann A, Steinke V, Vasen HF, Propping P, Sampson JR, Hes FJ, Aretz S.

Gastroenterology. 2009 Dec;137(6):1976-85.e1-10. doi: 10.1053/j.gastro.2009.08.052. Epub 2009 Sep 2.

PubMed [citation]

PMID:: 19732775

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000639350.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 216 of the MUTYH protein (p.Gly216Glu). This variant is present in population databases (rs768553551, gnomAD 0.006%). This missense change has been observed in individual(s) with MUTYH-related conditions (PMID: 18515411, 19732775, 20618354; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 231491). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Baylor Genetics, SCV004198926.2

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

From All of Us Research Program, National Institutes of Health, SCV004814570.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	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	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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