NM_001048174.2(MUTYH):c.565C>T (p.Arg189Cys) AND Familial adenomatous polyposis 2

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Feb 1, 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:: RCV000410783.16

Allele description [Variation Report for NM_001048174.2(MUTYH):c.565C>T (p.Arg189Cys)]

NM_001048174.2(MUTYH):c.565C>T (p.Arg189Cys)

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.565C>T (p.Arg189Cys)

HGVS:

NC_000001.11:g.45332615G>A
NG_008189.1:g.12856C>T
NM_001048171.2:c.565C>T
NM_001048172.2:c.568C>T
NM_001048173.2:c.565C>T
NM_001048174.2:c.565C>TMANE SELECT
NM_001128425.2:c.649C>T
NM_001293190.2:c.610C>T
NM_001293191.2:c.598C>T
NM_001293192.2:c.289C>T
NM_001293195.2:c.565C>T
NM_001293196.2:c.289C>T
NM_001350650.2:c.220C>T
NM_001350651.2:c.220C>T
NM_012222.3:c.640C>T
NP_001041636.1:p.Arg203Cys
NP_001041636.2:p.Arg189Cys
NP_001041637.1:p.Arg190Cys
NP_001041638.1:p.Arg189Cys
NP_001041639.1:p.Arg189Cys
NP_001121897.1:p.Arg217Cys
NP_001121897.1:p.Arg217Cys
NP_001280119.1:p.Arg204Cys
NP_001280120.1:p.Arg200Cys
NP_001280121.1:p.Arg97Cys
NP_001280124.1:p.Arg189Cys
NP_001280125.1:p.Arg97Cys
NP_001337579.1:p.Arg74Cys
NP_001337580.1:p.Arg74Cys
NP_036354.1:p.Arg214Cys
LRG_220t1:c.649C>T
LRG_220:g.12856C>T
LRG_220p1:p.Arg217Cys
NC_000001.10:g.45798287G>A
NM_001048171.1:c.607C>T
NM_001128425.1:c.649C>T
NR_146882.2:n.793C>T
NR_146883.2:n.642C>T
p.R217C

Protein change:

R189C

Links:

dbSNP: rs537292657

NCBI 1000 Genomes Browser:

rs537292657

Molecular consequence:

NM_001048171.2:c.565C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.568C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.565C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.565C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.649C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.610C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.598C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.289C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.565C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.289C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.220C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.220C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.640C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.793C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.642C>T - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000487333	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Uncertain significance (Jan 18, 2016)	unknown	clinical testing	mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000545731	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 3, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17949294, 28135145, 28492532
SCV000837769	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV004841637	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 1, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17949294, 28135145, 33471991, 25741868
SCV005056055	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 1, 2024)	unknown	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	5	not provided	not provided	108544	not provided	clinical testing
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

Olschwang S, Blanché H, de Moncuit C, Thomas G.

Genet Test. 2007 Fall;11(3):315-20.

PubMed [citation]

PMID:: 17949294

See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000487333.2

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

#	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 Invitae, SCV000545731.10

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

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 217 of the MUTYH protein (p.Arg217Cys). This variant is present in population databases (rs537292657, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of MUTYH related conditions (PMID: 17949294, 28135145; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.607C>T (p.Arg203Cys) and c.565C>T (p.Arg189Cys). ClinVar contains an entry for this variant (Variation ID: 184447). 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 Mendelics, SCV000837769.2

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

#	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, SCV004841637.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces arginine with cysteine at codon 217 of the MUTYH protein. This variant is also known as NM_001048171.1:c.607C>T (p.Arg203Cys) and NM_001048174.2:c.565C>T (p.Arg189Cys) in the literature. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer and in an individual affected with polyposis (PMID: 17949294, 28135145). In a large international case-control study, this variant was reported in 3/60466 breast cancer cases and 4/53461 controls (OR=0.663, 95%CI 0.148 to 2.963, p-value=0.713; PMID: 33471991). This variant has been identified in 12/251394 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	108544	not provided	not provided		5	not provided	not provided	not provided

From Baylor Genetics, SCV005056055.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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