NM_001048174.2(MUTYH):c.228C>A (p.Tyr76Ter) AND Familial adenomatous polyposis 2

Germline classification:: Pathogenic/Likely pathogenic (11 submissions)
Last evaluated:: Mar 22, 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:: RCV000005617.36

Allele description [Variation Report for NM_001048174.2(MUTYH):c.228C>A (p.Tyr76Ter)]

NM_001048174.2(MUTYH):c.228C>A (p.Tyr76Ter)

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.228C>A (p.Tyr76Ter)

HGVS:

NC_000001.11:g.45333449G>T
NG_008189.1:g.12022C>A
NM_001048171.2:c.228C>A
NM_001048172.2:c.231C>A
NM_001048173.2:c.228C>A
NM_001048174.2:c.228C>AMANE SELECT
NM_001128425.2:c.312C>A
NM_001293190.2:c.273C>A
NM_001293191.2:c.261C>A
NM_001293192.2:c.-49C>A
NM_001293195.2:c.228C>A
NM_001293196.2:c.-49C>A
NM_001350650.2:c.-44C>A
NM_001350651.2:c.-44C>A
NM_012222.3:c.303C>A
NP_001041636.1:p.Tyr90Ter
NP_001041636.2:p.Tyr76Ter
NP_001041637.1:p.Tyr77Ter
NP_001041638.1:p.Tyr76Ter
NP_001041639.1:p.Tyr76Ter
NP_001121897.1:p.Tyr104Ter
NP_001121897.1:p.Tyr104Ter
NP_001280119.1:p.Tyr91Ter
NP_001280120.1:p.Tyr87Ter
NP_001280124.1:p.Tyr76Ter
NP_036354.1:p.Tyr101Ter
LRG_220t1:c.312C>A
LRG_220:g.12022C>A
LRG_220p1:p.Tyr104Ter
NC_000001.10:g.45799121G>T
NM_001048171.1:c.270C>A
NM_001128425.1:c.312C>A
NR_146882.2:n.456C>A
NR_146883.2:n.379C>A
p.Tyr104*
p.Y104*

Protein change:

Y101*; TYR90TER

Links:

OMIM: 604933.0004; dbSNP: rs121908380

NCBI 1000 Genomes Browser:

rs121908380

Molecular consequence:

NM_001293192.2:c.-49C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001293196.2:c.-49C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350650.2:c.-44C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350651.2:c.-44C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NR_146882.2:n.456C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.379C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001048171.2:c.228C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001048172.2:c.231C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001048173.2:c.228C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001048174.2:c.228C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001128425.2:c.312C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001293190.2:c.273C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001293191.2:c.261C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001293195.2:c.228C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_012222.3:c.303C>A - nonsense - [Sequence Ontology: SO:0001587]

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

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gi|1370494432|ref|XP_024301837.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000025799	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2002)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000218794	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12393807, 19732775, 24444654, 28492532
SCV000246163	GeneReviews	no assertion criteria provided	Pathogenic (May 24, 2021)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 17369389, 23035301 J Med Genet. 2007,44:S100, Citation Link,
SCV000487327	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Pathogenic (Dec 22, 2015)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 18091433, 17219385, 25525159, 19732775, 18534194, 12393807 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000784261	Genomic Research Center, Shahid Beheshti University of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 5, 2018)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000919790	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 24, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19732775, 18534194 Citation Link,
SCV002564562	Arcensus	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 1, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004015248	KCCC/NGS Laboratory, Kuwait Cancer Control Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 7, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004199409	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 22, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004837920	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 3, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 12393807, 17273161, 17369389, 18091433, 18534194, 18564191, 19279422, 19732775, 22976915, 24444654, 27705013, 27829682, 25741868
SCV004847995	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 3, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17369389, 18534194, 12393807, 19732775, 27829682, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	inherited	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	3	not provided	not provided	108544	not provided	clinical testing, literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

MUTYH Polyposis.

Nielsen M, Infante E, Brand R.

2012 Oct 4 [updated 2021 May 27]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 23035301

See all PubMed Citations (17)

Details of each submission

From OMIM, SCV000025799.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a Pakistani patient with multiple colorectal adenomas (FAP2; 608456), Jones et al. (2002) identified homozygosity for a 270C-A mutation in exon 3 of the MUTYH gene, resulting in a tyr90-to-ter (Y90X) substitution.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000218794.12

#	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 creates a premature translational stop signal (p.Tyr104*) in the MUTYH gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs121908380, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with colorectal cancer and MUTYH-associated polyposis syndrome (PMID: 12393807, 19732775, 24444654). This variant is also known as p.Tyr90*. ClinVar contains an entry for this variant (Variation ID: 5296). Studies have shown that this premature translational stop signal results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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

From GeneReviews, SCV000246163.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

Common in Pakistani population

#	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 Counsyl, SCV000487327.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

#	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 Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV000784261.2

#	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	inherited	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919790.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: The MUTYH c.312C>A (p.Tyr104X) variant results in a premature termination codon, predicted to cause a truncated or absent MUTYH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1147delC, p.Ala385fsX23; c.1227_1228dupGG, p.Glu410fsX43). One in silico tool predicts a damaging outcome for this variant. This variant was found in 31/277196 control chromosomes at a frequency of 0.0001118, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). The variant has been reported in numerous affected individuals in the literature in the homozygous and compound heterozygous state, and has been shown to be completely devoid of both glycosylase and DNA binding activities (Ali_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, 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 Arcensus, SCV002564562.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From KCCC/NGS Laboratory, Kuwait Cancer Control Center, SCV004015248.1

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

Description

MUTYH Tyr104Ter: This sequence change creates a premature translational stop signal (p.Tyr104*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. Null variant (nonsense) in the MUTYH gene is a known mechanism of disease (PMID: 18534194, 20663686). This variant has been observed in an individual affected with colorectal cancer (PMID: 24444654) and as homozygous in several individuals affected with MUTYH-associated polyposis syndrome (PMID: 12393807, 19732775). This variant is also known as p.Tyr90* in the literature. ClinVar classifies this variant as Pathogenic, rated 2 stars, with 12 submissions, 17 publications (12393807, 17219385, 17273161, 17369389, 18091433 and 12 more) and no conflicts. Therefore, this variant has been classified as Pathogenic.

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

From Baylor Genetics, SCV004199409.2

#	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, SCV004837920.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (13)

Description

This variant changes 1 nucleotide in exon 3 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant resulted in no detectable glycolysase activity or DNA binding in protein extracts (PMID: 18534194). This variant has been reported in biallelic individuals affected with MUTYH-associated polyposis (PMID: 12393807, 17273161, 17369389, 18091433, 18564191, 19279422, 19732775, 22976915, 24444654, 27705013, 27829682). This variant has been identified in 31/282862 chromosomes 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	108544	not provided	not provided		3	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847995.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The p.Try104X (historically referred to as Y90X) variant in MUTYH has been reported in at least 2 homozygotes or 5 compound heterozygotes with another pathogenic variant and multiple colorectal adenomas or MYH-associated polyposis (Jones 2002 PMID: 12393807, Sampson 2003 PMID: 12853198, Gregorio 2006 PMID: 16890597, Ponti 2007 PMID: 17273161; Croitoru 2007 PMID: 17219385). It has also been reported by other clinical laboratories in ClinVar (Variation ID 5296). Additionally, it has been identified in 1/4826 South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 104 and was shown to produce no protein when cloned into an expression vector and expressed in BL21 CodonPlus (DE3) RIL E. coli (Ali 2009 PMID: 18534194). Function studies from these cells showed this variant was completely devoid of both glycosylase and DNA binding activities (Ali 2009 PMID: 18534194). Loss of function of the MUTYH gene is an established disease mechanism in autosomal recessive MYH-associated polyposis. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MYH-associated polyposis. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PM2_Supporting, PS3_Supporting.

#	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: Oct 8, 2024

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