NM_001048174.2(MUTYH):c.1217C>T (p.Thr406Met) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 21, 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:: RCV000115757.17

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1217C>T (p.Thr406Met)]

NM_001048174.2(MUTYH):c.1217C>T (p.Thr406Met)

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.1217C>T (p.Thr406Met)

Other names:

p.T434M:ACG>ATG

HGVS:

NC_000001.11:g.45331442G>A
NG_008189.1:g.14029C>T
NM_001048171.2:c.1217C>T
NM_001048172.2:c.1220C>T
NM_001048173.2:c.1217C>T
NM_001048174.2:c.1217C>TMANE SELECT
NM_001128425.2:c.1301C>T
NM_001293190.2:c.1262C>T
NM_001293191.2:c.1250C>T
NM_001293192.2:c.941C>T
NM_001293195.2:c.1217C>T
NM_001293196.2:c.941C>T
NM_001350650.2:c.872C>T
NM_001350651.2:c.872C>T
NM_012222.3:c.1292C>T
NP_001041636.1:p.Thr420Met
NP_001041636.2:p.Thr406Met
NP_001041637.1:p.Thr407Met
NP_001041638.1:p.Thr406Met
NP_001041639.1:p.Thr406Met
NP_001121897.1:p.Thr434Met
NP_001121897.1:p.Thr434Met
NP_001280119.1:p.Thr421Met
NP_001280120.1:p.Thr417Met
NP_001280121.1:p.Thr314Met
NP_001280124.1:p.Thr406Met
NP_001280125.1:p.Thr314Met
NP_001337579.1:p.Thr291Met
NP_001337580.1:p.Thr291Met
NP_036354.1:p.Thr431Met
LRG_220t1:c.1301C>T
LRG_220:g.14029C>T
LRG_220p1:p.Thr434Met
NC_000001.10:g.45797114G>A
NM_001048171.1:c.1259C>T
NM_001128425.1:c.1301C>T
NR_146882.2:n.1445C>T
NR_146883.2:n.1294C>T
p.T434M

Protein change:

T291M

Links:

dbSNP: rs587780084

NCBI 1000 Genomes Browser:

rs587780084

Molecular consequence:

NM_001048171.2:c.1217C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.1220C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.1217C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.1217C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.1301C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.1262C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.1250C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.941C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.1217C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.941C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.872C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.872C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.1292C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.1445C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.1294C>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
SCV000184172	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 21, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25980754, 28944238, 33471991 Citation Link,
SCV000690516	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 7, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25980754, 28135145, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184172

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jun 21, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000690516

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 7, 2022)

germline

clinical testing

PubMed (3)
[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

Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes.

DeRycke MS, Gunawardena S, Balcom JR, Pickart AM, Waltman LA, French AJ, McDonnell S, Riska SM, Fogarty ZC, Larson MC, Middha S, Eckloff BW, Asmann YW, Ferber MJ, Haile RW, Gallinger S, Clendenning M, Rosty C, Win AK, Buchanan DD, Hopper JL, Newcomb PA, et al.

Mol Genet Genomic Med. 2017 Sep;5(5):553-569. doi: 10.1002/mgg3.317.

PubMed [citation]

PMID:: 28944238
PMCID:: PMC5606870

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 (5)

Details of each submission

From Ambry Genetics, SCV000184172.9

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

Description

The p.T434M variant (also known as c.1301C>T), located in coding exon 13 of the MUTYH gene, results from a C to T substitution at nucleotide position 1301. The threonine at codon 434 is replaced by methionine, an amino acid with similar properties. This alteration was identified in a cohort of 1,260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology 2015 Sep;149(3):604-613.e20). This alteration was also reported in 9/60,466 breast cancer cases as well as 5/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Additionally, this alteration was identified in an individual diagnosed with colorectal cancer (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This amino acid position is not 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, SCV000690516.5

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

Description

This missense variant replaces threonine with methionine at codon 434 of the MUTYH protein. This variant is also known as c.1259C>T (p.Thr420Met) based on the NM_001048171.1 transcript. 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 suspected of having Lynch syndrome (PMID: 25980754) and in an individual affected with colorectal cancer (PMID: 28135145). This variant has also been identified in 11/282736 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: May 7, 2024

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