NM_001048174.2(MUTYH):c.2T>C (p.Met1Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Apr 18, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000571566.11

Allele description [Variation Report for NM_001048174.2(MUTYH):c.2T>C (p.Met1Thr)]

NM_001048174.2(MUTYH):c.2T>C (p.Met1Thr)

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.2T>C (p.Met1Thr)

HGVS:

NC_000001.11:g.45334504A>G
NG_008189.1:g.10967T>C
NM_001048171.2:c.2T>C
NM_001048172.2:c.2T>C
NM_001048173.2:c.2T>C
NM_001048174.2:c.2T>CMANE SELECT
NM_001128425.2:c.44T>C
NM_001293190.2:c.44T>C
NM_001293191.2:c.2T>C
NM_001293192.2:c.-211T>C
NM_001293195.2:c.2T>C
NM_001293196.2:c.-211T>C
NM_001350650.2:c.-270T>C
NM_001350651.2:c.-206T>C
NM_012222.3:c.44T>C
NP_001041636.2:p.Met1Thr
NP_001041637.1:p.Met1Thr
NP_001041638.1:p.Met1Thr
NP_001041639.1:p.Met1Thr
NP_001121897.1:p.Met15Thr
NP_001121897.1:p.Met15Thr
NP_001280119.1:p.Met15Thr
NP_001280120.1:p.Met1Thr
NP_001280124.1:p.Met1Thr
NP_036354.1:p.Met15Thr
LRG_220t1:c.44T>C
LRG_220:g.10967T>C
LRG_220p1:p.Met15Thr
NC_000001.10:g.45800176A>G
NM_001128425.1:c.44T>C
NR_146882.2:n.230T>C
NR_146883.2:n.153T>C

Protein change:

M15T

Links:

dbSNP: rs201163858

NCBI 1000 Genomes Browser:

rs201163858

Molecular consequence:

NM_001293192.2:c.-211T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001293196.2:c.-211T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350650.2:c.-270T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350651.2:c.-206T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001048171.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001048172.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001048173.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001048174.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001293191.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001293195.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001048171.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.44T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.44T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.44T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.230T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.153T>C - 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
SCV000666473	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 15, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001344067	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 18, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000666473

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 15, 2023)

germline

clinical testing

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

Citation Link,

SCV001344067

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 18, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Exome sequencing identifies MUTYH mutations in a family with colorectal cancer and an atypical phenotype.

Seguí N, Navarro M, Pineda M, Köger N, Bellido F, González S, Campos O, Iglesias S, Valdés-Mas R, López-Doriga A, Gut M, Blanco I, Lázaro C, Capellá G, Puente XS, Plotz G, Valle L.

Gut. 2015 Feb;64(2):355-6. doi: 10.1136/gutjnl-2014-307084. Epub 2014 Apr 1. No abstract available.

PubMed [citation]

PMID:: 24691292

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000666473.7

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

Description

The p.M15T pathogenic mutation (also known as c.44T>C), located in coding exon 2 of the MUTYH gene, results from a T to C substitution at nucleotide position 44. The methionine at codon 15 is replaced by threonine, an amino acid with similar properties. This variant has been identified with a second MUTYH pathogenic variant in multiple individuals with clinical features of MUTYH-associated polyposis (Ambry internal data). Another alteration at the same codon, p.M15V, has been reported as co-occurring with a pathogenic MUTYH mutation in three siblings with colorectal cancer in their forties and a history of multiple adenomas in their fifties and sixties (Seguí N et al. Gut. 2015 Feb;64:355-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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, SCV001344067.3

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

Description

This missense variant replaces methionine with threonine at codon 15 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 33471991). This variant has been identified in 2/251474 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

Last Updated: Jun 23, 2024

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