NM_001048174.2(MUTYH):c.519G>T (p.Met173Ile) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 7, 2022
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:: RCV000561894.8

Allele description [Variation Report for NM_001048174.2(MUTYH):c.519G>T (p.Met173Ile)]

NM_001048174.2(MUTYH):c.519G>T (p.Met173Ile)

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.519G>T (p.Met173Ile)

HGVS:

NC_000001.11:g.45332661C>A
NG_008189.1:g.12810G>T
NM_001048171.2:c.519G>T
NM_001048172.2:c.522G>T
NM_001048173.2:c.519G>T
NM_001048174.2:c.519G>TMANE SELECT
NM_001128425.2:c.603G>T
NM_001293190.2:c.564G>T
NM_001293191.2:c.552G>T
NM_001293192.2:c.243G>T
NM_001293195.2:c.519G>T
NM_001293196.2:c.243G>T
NM_001350650.2:c.174G>T
NM_001350651.2:c.174G>T
NM_012222.3:c.594G>T
NP_001041636.2:p.Met173Ile
NP_001041637.1:p.Met174Ile
NP_001041638.1:p.Met173Ile
NP_001041639.1:p.Met173Ile
NP_001121897.1:p.Met201Ile
NP_001121897.1:p.Met201Ile
NP_001280119.1:p.Met188Ile
NP_001280120.1:p.Met184Ile
NP_001280121.1:p.Met81Ile
NP_001280124.1:p.Met173Ile
NP_001280125.1:p.Met81Ile
NP_001337579.1:p.Met58Ile
NP_001337580.1:p.Met58Ile
NP_036354.1:p.Met198Ile
LRG_220t1:c.603G>T
LRG_220:g.12810G>T
LRG_220p1:p.Met201Ile
NC_000001.10:g.45798333C>A
NM_001128425.1:c.603G>T
NR_146882.2:n.747G>T
NR_146883.2:n.596G>T

Protein change:

M173I

Links:

dbSNP: rs1172521297

NCBI 1000 Genomes Browser:

rs1172521297

Molecular consequence:

NM_001048171.2:c.519G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.522G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.519G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.519G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.603G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.564G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.552G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.243G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.519G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.243G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.174G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.174G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.594G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.747G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.596G>T - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000666454	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Dec 7, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000690593	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 27, 2019)	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

SCV000666454

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Dec 7, 2022)

germline

clinical testing

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

Citation Link,

SCV000690593

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 27, 2019)

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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures.

Georgeson P, Harrison TA, Pope BJ, Zaidi SH, Qu C, Steinfelder RS, Lin Y, Joo JE, Mahmood K, Clendenning M, Walker R, Amitay EL, Berndt SI, Brenner H, Campbell PT, Cao Y, Chan AT, Chang-Claude J, Doheny KF, Drew DA, Figueiredo JC, French AJ, et al.

Nat Commun. 2022 Jun 6;13(1):3254. doi: 10.1038/s41467-022-30916-1.

PubMed [citation]

PMID:: 35668106
PMCID:: PMC9170691

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Ambry Genetics, SCV000666454.6

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

Description

The p.M201I variant (also known as c.603G>T), located in coding exon 8 of the MUTYH gene, results from a G to T substitution at nucleotide position 603. The methionine at codon 201 is replaced by isoleucine, an amino acid with highly similar properties. This variant was identified in the germline along with MUTYH p.R474C (c.1420C>T) in a patient in the 80-89 year old age group with colorectal cancer (Georgeson P et al. Nat Commun, 2022 Jun;13:3254). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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, SCV000690593.3

#	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

Last Updated: May 1, 2024

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