NM_001048174.2(MUTYH):c.1193G>T (p.Arg398Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 22, 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:: RCV000219054.10

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1193G>T (p.Arg398Leu)]

NM_001048174.2(MUTYH):c.1193G>T (p.Arg398Leu)

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.1193G>T (p.Arg398Leu)

HGVS:

NC_000001.11:g.45331466C>A
NG_008189.1:g.14005G>T
NM_001048171.2:c.1193G>T
NM_001048172.2:c.1196G>T
NM_001048173.2:c.1193G>T
NM_001048174.2:c.1193G>TMANE SELECT
NM_001128425.2:c.1277G>T
NM_001293190.2:c.1238G>T
NM_001293191.2:c.1226G>T
NM_001293192.2:c.917G>T
NM_001293195.2:c.1193G>T
NM_001293196.2:c.917G>T
NM_001350650.2:c.848G>T
NM_001350651.2:c.848G>T
NM_012222.3:c.1268G>T
NP_001041636.1:p.Arg412Leu
NP_001041636.2:p.Arg398Leu
NP_001041637.1:p.Arg399Leu
NP_001041638.1:p.Arg398Leu
NP_001041639.1:p.Arg398Leu
NP_001121897.1:p.Arg426Leu
NP_001121897.1:p.Arg426Leu
NP_001280119.1:p.Arg413Leu
NP_001280120.1:p.Arg409Leu
NP_001280121.1:p.Arg306Leu
NP_001280124.1:p.Arg398Leu
NP_001280125.1:p.Arg306Leu
NP_001337579.1:p.Arg283Leu
NP_001337580.1:p.Arg283Leu
NP_036354.1:p.Arg423Leu
LRG_220t1:c.1277G>T
LRG_220:g.14005G>T
LRG_220p1:p.Arg426Leu
NC_000001.10:g.45797138C>A
NM_001048171.1:c.1235G>T
NM_001128425.1:c.1277G>T
NR_146882.2:n.1421G>T
NR_146883.2:n.1270G>T

Protein change:

R283L

Links:

dbSNP: rs748700385

NCBI 1000 Genomes Browser:

rs748700385

Molecular consequence:

NM_001048171.2:c.1193G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.1196G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.1193G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.1193G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.1277G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.1238G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.1226G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.917G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.1193G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.917G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.848G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.848G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.1268G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.1421G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.1270G>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
SCV000278437	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Dec 22, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16134147, 16557584, 33471991 Citation Link,
SCV000685561	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 2, 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

SCV000278437

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Dec 22, 2023)

germline

clinical testing

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

Citation Link,

SCV000685561

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 2, 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

Mutations of APC and MYH in unrelated Italian patients with adenomatous polyposis coli.

Aceto G, Curia MC, Veschi S, De Lellis L, Mammarella S, Catalano T, Stuppia L, Palka G, Valanzano R, Tonelli F, Casale V, Stigliano V, Cetta F, Battista P, Mariani-Costantini R, Cama A.

Hum Mutat. 2005 Oct;26(4):394.

PubMed [citation]

PMID:: 16134147

MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype.

Aretz S, Uhlhaas S, Goergens H, Siberg K, Vogel M, Pagenstecher C, Mangold E, Caspari R, Propping P, Friedl W.

Int J Cancer. 2006 Aug 15;119(4):807-14.

PubMed [citation]

PMID:: 16557584

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000278437.7

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

Description

The p.R426L variant (also known as c.1277G>T), located in coding exon 13 of the MUTYH gene, results from a G to T substitution at nucleotide position 1277. The arginine at codon 426 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported in 2/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is poorly 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, SCV000685561.5

#	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 arginine with leucine at codon 426 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 performed for this variant. In a large international case-control study, this variant was reported in 2/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 1/251262 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: Sep 29, 2024

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