NM_001048174.2(MUTYH):c.1102+1G>A AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Aug 28, 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:: RCV000129098.6

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1102+1G>A]

NM_001048174.2(MUTYH):c.1102+1G>A

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.1102+1G>A

HGVS:

NC_000001.11:g.45331660C>T
NG_008189.1:g.13811G>A
NM_001048171.2:c.1102+1G>A
NM_001048172.2:c.1105+1G>A
NM_001048173.2:c.1102+1G>A
NM_001048174.2:c.1102+1G>AMANE SELECT
NM_001128425.2:c.1186+1G>A
NM_001293190.2:c.1147+1G>A
NM_001293191.2:c.1135+1G>A
NM_001293192.2:c.826+1G>A
NM_001293195.2:c.1102+1G>A
NM_001293196.2:c.826+1G>A
NM_001350650.2:c.757+1G>A
NM_001350651.2:c.757+1G>A
NM_001407069.1:c.1135+1G>A
NM_001407070.1:c.1102+1G>A
NM_001407071.1:c.1105+1G>A
NM_001407072.1:c.1102+1G>A
NM_001407073.1:c.1102+1G>A
NM_001407075.1:c.1018+1G>A
NM_001407077.1:c.1135+1G>A
NM_001407078.1:c.1105+1G>A
NM_001407079.1:c.1063+1G>A
NM_001407080.1:c.1060+1G>A
NM_001407081.1:c.1102+1G>A
NM_001407082.1:c.757+1G>A
NM_001407083.1:c.1144+1G>A
NM_001407085.1:c.1144+1G>A
NM_001407086.1:c.1105+1G>A
NM_001407087.1:c.1123+1G>A
NM_001407088.1:c.1102+1G>A
NM_001407089.1:c.1102+1G>A
NM_001407091.1:c.826+1G>A
NM_012222.3:c.1177+1G>A
LRG_220t1:c.1186+1G>A
LRG_220:g.13811G>A
NC_000001.10:g.45797332C>T
NM_001128425.1:c.1186+1G>A

Links:

dbSNP: rs587781337

NCBI 1000 Genomes Browser:

rs587781337

Molecular consequence:

NM_001048171.2:c.1102+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001048172.2:c.1105+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001048173.2:c.1102+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001048174.2:c.1102+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001128425.2:c.1186+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001293190.2:c.1147+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001293191.2:c.1135+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001293192.2:c.826+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001293195.2:c.1102+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001293196.2:c.826+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001350650.2:c.757+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001350651.2:c.757+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407069.1:c.1135+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407070.1:c.1102+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407071.1:c.1105+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407072.1:c.1102+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407073.1:c.1102+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407075.1:c.1018+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407077.1:c.1135+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407078.1:c.1105+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407079.1:c.1063+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407080.1:c.1060+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407081.1:c.1102+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407082.1:c.757+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407083.1:c.1144+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407085.1:c.1144+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407086.1:c.1105+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407087.1:c.1123+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407088.1:c.1102+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407089.1:c.1102+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407091.1:c.826+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_012222.3:c.1177+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000183809	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 2, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004358557	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 28, 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

SCV000183809

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 2, 2021)

germline

clinical testing

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

Citation Link,

SCV004358557

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 28, 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

Structural Basis for Finding OG Lesions and Avoiding Undamaged G by the DNA Glycosylase MutY.

Russelburg LP, O'Shea Murray VL, Demir M, Knutsen KR, Sehgal SL, Cao S, David SS, Horvath MP.

ACS Chem Biol. 2020 Jan 17;15(1):93-102. doi: 10.1021/acschembio.9b00639. Epub 2019 Dec 27.

PubMed [citation]

PMID:: 31829624
PMCID:: PMC7069122

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, SCV000183809.8

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

Description

The c.1186+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 12 of the MUTYH gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of the missing amino acids is unknown; however, based on an internal structural analysis, coding exon 12 skipping would disrupt the structure of the NUDIX domain (Ambry internal data; Russelburg LP et al. ACS Chem Biol, 2020 01;15:93-102). This variant was identified in conjunction with a pathogenic MUTYH variant in a proband with adenomatous polyposis, but the phase of the two variants was unknown (Ambry internal data). 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, SCV004358557.1

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

Description

This variant causes a G>A nucleotide substitution at the +1 position of intron 12 of the MUTYH gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, RNA studies have not been published for this variant, however it is expected to result in the skipping of exon 12 (ClinVar: SCV000941079.5). Pathogenic missense variants have been identified in exon 12 (ClinVar Variation IDs: 406845, 421574), indicating this exon is important for function. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 1/249520 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	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: Oct 8, 2024

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