NM_001048174.2(MUTYH):c.565C>T (p.Arg189Cys) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 30, 2018
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:: RCV000508296.4

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]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000601655	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Apr 13, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000919795	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Apr 30, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28135145, 17949294 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000601655

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Apr 13, 2017)

germline

clinical testing

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

SCV000919795

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Apr 30, 2018)

germline

clinical testing

PubMed (2)
[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

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.

Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, Ukaegbu CI, Brais LK, McNamara PG, Mayer RJ, Schrag D, Meyerhardt JA, Ng K, Kidd J, Singh N, Hartman AR, Wenstrup RJ, Syngal S.

J Clin Oncol. 2017 Apr 1;35(10):1086-1095. doi: 10.1200/JCO.2016.71.0012. Epub 2017 Jan 30.

PubMed [citation]

PMID:: 28135145
PMCID:: PMC5455355

See all PubMed Citations (3)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601655.2

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919795.1

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

Description

Variant summary: MUTYH c.649C>T (p.Arg217Cys) results in a non-conservative amino acid change located in the HhH-GPD_domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. This frequency is lower than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (4.9e-05 vs 0.0046), allowing no conclusion about variant significance. The c.649C>T has been reported in the literature in individuals affected with multiple colorectal adenomas. These reports do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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

Last Updated: Sep 29, 2024

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