NM_001048174.2(MUTYH):c.1165C>T (p.Arg389Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 29, 2024
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:: RCV000164662.11

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1165C>T (p.Arg389Cys)]

NM_001048174.2(MUTYH):c.1165C>T (p.Arg389Cys)

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.1165C>T (p.Arg389Cys)

HGVS:

NC_000001.11:g.45331494G>A
NG_008189.1:g.13977C>T
NM_001048171.2:c.1165C>T
NM_001048172.2:c.1168C>T
NM_001048173.2:c.1165C>T
NM_001048174.2:c.1165C>TMANE SELECT
NM_001128425.2:c.1249C>T
NM_001293190.2:c.1210C>T
NM_001293191.2:c.1198C>T
NM_001293192.2:c.889C>T
NM_001293195.2:c.1165C>T
NM_001293196.2:c.889C>T
NM_001350650.2:c.820C>T
NM_001350651.2:c.820C>T
NM_012222.3:c.1240C>T
NP_001041636.2:p.Arg389Cys
NP_001041637.1:p.Arg390Cys
NP_001041638.1:p.Arg389Cys
NP_001041639.1:p.Arg389Cys
NP_001121897.1:p.Arg417Cys
NP_001121897.1:p.Arg417Cys
NP_001280119.1:p.Arg404Cys
NP_001280120.1:p.Arg400Cys
NP_001280121.1:p.Arg297Cys
NP_001280124.1:p.Arg389Cys
NP_001280125.1:p.Arg297Cys
NP_001337579.1:p.Arg274Cys
NP_001337580.1:p.Arg274Cys
NP_036354.1:p.Arg414Cys
LRG_220t1:c.1249C>T
LRG_220:g.13977C>T
LRG_220p1:p.Arg417Cys
NC_000001.10:g.45797166G>A
NM_001128425.1:c.1249C>T
NR_146882.2:n.1393C>T
NR_146883.2:n.1242C>T
p.R417C

Protein change:

R274C

Links:

dbSNP: rs773370513

NCBI 1000 Genomes Browser:

rs773370513

Molecular consequence:

NM_001048171.2:c.1165C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.1168C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.1165C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.1165C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.1249C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.1210C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.1198C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.889C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.1165C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.889C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.820C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.820C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.1240C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.1393C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.1242C>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
SCV000215327	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 29, 2024)	germline	clinical testing	Citation Link,
SCV002052689	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 30, 2023)	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

SCV000215327

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Apr 29, 2024)

germline

clinical testing

Citation Link,

SCV002052689

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 30, 2023)

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

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, SCV000215327.8

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

Description

The p.R417C variant (also known as c.1249C>T), located in coding exon 13 of the MUTYH gene, results from a C to T substitution at nucleotide position 1249. The arginine at codon 417 is replaced by cysteine, an amino acid with highly dissimilar properties. 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. Based on the available evidence, the clinical significance of this variant 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, SCV002052689.2

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

Description

This missense variant replaces arginine with cysteine at codon 417 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 not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 7/282458 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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