NM_001048174.2(MUTYH):c.1434+1G>A AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jan 5, 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:: RCV003585649.2

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1434+1G>A]

NM_001048174.2(MUTYH):c.1434+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.1434+1G>A

HGVS:

NC_000001.11:g.45330515C>T
NG_008189.1:g.14956G>A
NM_001048171.2:c.1434+1G>A
NM_001048172.2:c.1437+1G>A
NM_001048173.2:c.1434+1G>A
NM_001048174.2:c.1434+1G>AMANE SELECT
NM_001128425.2:c.1518+1G>A
NM_001293190.2:c.1479+1G>A
NM_001293191.2:c.1467+1G>A
NM_001293192.2:c.1158+1G>A
NM_001293195.2:c.1434+1G>A
NM_001293196.2:c.1158+1G>A
NM_001350650.2:c.1089+1G>A
NM_001350651.2:c.1089+1G>A
NM_001407069.1:c.1467+1G>A
NM_001407070.1:c.1434+1G>A
NM_001407071.1:c.1437+1G>A
NM_001407072.1:c.1434+1G>A
NM_001407073.1:c.1434+1G>A
NM_001407075.1:c.1350+1G>A
NM_001407077.1:c.1467+1G>A
NM_001407078.1:c.1437+1G>A
NM_001407079.1:c.1395+1G>A
NM_001407080.1:c.1392+1G>A
NM_001407081.1:c.1434+1G>A
NM_001407082.1:c.1089+1G>A
NM_001407083.1:c.1476+1G>A
NM_001407085.1:c.1476+1G>A
NM_001407086.1:c.1437+1G>A
NM_001407087.1:c.1455+1G>A
NM_001407088.1:c.1434+1G>A
NM_001407089.1:c.1434+1G>A
NM_001407091.1:c.1158+1G>A
NM_012222.3:c.1509+1G>A
LRG_220:g.14956G>A
NC_000001.10:g.45796187C>T
NM_001128425.1:c.1518+1G>A

Molecular consequence:

NM_001048171.2:c.1434+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001048172.2:c.1437+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001048173.2:c.1434+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001048174.2:c.1434+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001128425.2:c.1518+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001293190.2:c.1479+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001293191.2:c.1467+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001293192.2:c.1158+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001293195.2:c.1434+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001293196.2:c.1158+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001350650.2:c.1089+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001350651.2:c.1089+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407069.1:c.1467+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407070.1:c.1434+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407071.1:c.1437+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407072.1:c.1434+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407073.1:c.1434+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407075.1:c.1350+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407077.1:c.1467+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407078.1:c.1437+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407079.1:c.1395+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407080.1:c.1392+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407081.1:c.1434+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407082.1:c.1089+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407083.1:c.1476+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407085.1:c.1476+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407086.1:c.1437+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407087.1:c.1455+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407088.1:c.1434+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407089.1:c.1434+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407091.1:c.1158+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_012222.3:c.1509+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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semaphorin-3C [Chlorocebus sabaeus]
semaphorin-3C [Chlorocebus sabaeus]
gi|635115200|ref|XP_007980552.1|

Protein
PREDICTED: Chlorocebus sabaeus semaphorin 3C (SEMA3C), transcript variant X1, mR...
PREDICTED: Chlorocebus sabaeus semaphorin 3C (SEMA3C), transcript variant X1, mRNA
gi|1938862197|ref|XM_007982361.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004357793	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 3, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005037982	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jan 5, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004357793

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 3, 2023)

germline

clinical testing

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

SCV005037982

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jan 5, 2024)

germline

clinical testing

Citation Link

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 Color Diagnostics, LLC DBA Color Health, SCV004357793.1

#	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 to A nucleotide substitution at the +1 position of intron 15 of the MUTYH gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. 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. Other variants occurring at the same position and at the same donor site are considered disease causing in ClinVar (Variation IDs: 231877, 1324752, 1499267). This variant has not been identified 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

From Ambry Genetics, SCV005037982.1

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

Description

The c.1518+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 15 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. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be 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: May 7, 2024

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Relating variation to medicine