NM_001048174.2(MUTYH):c.566G>A (p.Arg189His) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: May 8, 2023
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:: RCV000129023.15

Allele description [Variation Report for NM_001048174.2(MUTYH):c.566G>A (p.Arg189His)]

NM_001048174.2(MUTYH):c.566G>A (p.Arg189His)

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.566G>A (p.Arg189His)

HGVS:

NC_000001.11:g.45332614C>T
NG_008189.1:g.12857G>A
NM_001048171.2:c.566G>A
NM_001048172.2:c.569G>A
NM_001048173.2:c.566G>A
NM_001048174.2:c.566G>AMANE SELECT
NM_001128425.2:c.650G>A
NM_001293190.2:c.611G>A
NM_001293191.2:c.599G>A
NM_001293192.2:c.290G>A
NM_001293195.2:c.566G>A
NM_001293196.2:c.290G>A
NM_001350650.2:c.221G>A
NM_001350651.2:c.221G>A
NM_012222.3:c.641G>A
NP_001041636.1:p.Arg203His
NP_001041636.2:p.Arg189His
NP_001041637.1:p.Arg190His
NP_001041638.1:p.Arg189His
NP_001041639.1:p.Arg189His
NP_001121897.1:p.Arg217His
NP_001121897.1:p.Arg217His
NP_001280119.1:p.Arg204His
NP_001280120.1:p.Arg200His
NP_001280121.1:p.Arg97His
NP_001280124.1:p.Arg189His
NP_001280125.1:p.Arg97His
NP_001337579.1:p.Arg74His
NP_001337580.1:p.Arg74His
NP_036354.1:p.Arg214His
LRG_220t1:c.650G>A
LRG_220:g.12857G>A
LRG_220p1:p.Arg217His
NC_000001.10:g.45798286C>T
NM_001048171.1:c.608G>A
NM_001128425.1:c.650G>A
NR_146882.2:n.794G>A
NR_146883.2:n.643G>A
p.R217H

Protein change:

R189H

Links:

dbSNP: rs147754007

NCBI 1000 Genomes Browser:

rs147754007

Molecular consequence:

NM_001048171.2:c.566G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.569G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.566G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.566G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.650G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.611G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.599G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.290G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.566G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.290G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.221G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.221G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.641G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.794G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.643G>A - 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

Recent activity

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Nucleotide
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Ponticola bathybius isolate FTG147 cytochrome b (cytb) gene, partial cds; mitochondrial
gi|1914871188|gb|MN813628.1|

Nucleotide
beta-1,4-N-acetyl-galactosaminyl transferase 1, isoform CRA_a [Mus musculus]
beta-1,4-N-acetyl-galactosaminyl transferase 1, isoform CRA_a [Mus musculus]
gi|148692526|gb|EDL24473.1||gnl|WGS |mCP94709

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000172924	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Dec 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000685654	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 8, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11051386, 17949294, 26556299, 33130102, 33471991, 35980532, 25741868
SCV002532309	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Dec 7, 2021)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 17949294, 33130102, 25307848, 33471991 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000172924

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Dec 1, 2022)

germline

clinical testing

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

Citation Link,

SCV000685654

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 8, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV002532309

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Dec 7, 2021)

germline

curation

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

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, curation

Citations

PubMed

Antimycobacterial therapy for Crohn's disease.

Gilad J.

Am J Gastroenterol. 2000 Oct;95(10):2985-6. No abstract available.

PubMed [citation]

PMID:: 11051386

Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA.

Schrader KA, Cheng DT, Joseph V, Prasad M, Walsh M, Zehir A, Ni A, Thomas T, Benayed R, Ashraf A, Lincoln A, Arcila M, Stadler Z, Solit D, Hyman DM, Zhang L, Klimstra D, Ladanyi M, Offit K, Berger M, Robson M.

JAMA Oncol. 2016 Jan;2(1):104-11. doi: 10.1001/jamaoncol.2015.5208. Erratum in: JAMA Oncol. 2016 Feb;2(2):279. doi: 10.1001/jamaoncol.2015.6541. Hyman, David [corrected to Hyman, David M].

PubMed [citation]

PMID:: 26556299
PMCID:: PMC5477989

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000172924.9

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

Description

The p.R217H variant (also known as c.650G>A), located in coding exon 8 of the MUTYH gene, results from a G to A substitution at nucleotide position 650. The arginine at codon 217 is replaced by histidine, an amino acid with highly similar properties. This alteration, designated as p.Arg203His, has been reported as a variant of unknown significance in an adenomatous polyposis cohort (Olschwang S et al. Genet. Test. 2007;11:315-20). In a different study, this alteration was detected in a large Austrian kindred with familial colorectal cancer type X (FCCTX) in conjunction with a SEMA4A gene alteration; this alteration did not segregate with colorectal cancer in the family whereas the SEMA4A gene alteration did (Schulz E et al. Nat Commun. 2014 Oct 13;5:5191). In addition, this alteration was detected in the germline of an individual with advanced cancer who underwent tumor-normal sequencing; although clinical details were not provided, authors noted that the patient's phenotypic expression was not consistent with an autosomal recessive mode of inheritance (Schrader KA et al. JAMA Oncol. 2016 Jan;2(1):104-11). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000685654.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant replaces arginine with histidine at codon 217 of the MUTYH protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in the compound heterozygous state in an individual affected with MUTYH-associated polyposis (PMID: 33130102). This variant has also been reported in an individual affected with colorectal adenomas (PMID 17949294), a family with familial colorectal cancer (however, the variant did not segregate with the disease; PMID 25307848), an individual with unspecified cancer (PMID: 26556299), individuals affected with breast cancer, and healthy controls (PMID: 33471991, 35980532; DOI: 10.3390/biomedicines11051386). This variant has been identified in 11/282760 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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 Sema4, Sema4, SCV002532309.1

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

#	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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