NM_001048174.2(MUTYH):c.1171G>A (p.Ala391Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Dec 7, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000130485.19

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1171G>A (p.Ala391Thr)]

NM_001048174.2(MUTYH):c.1171G>A (p.Ala391Thr)

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.1171G>A (p.Ala391Thr)

HGVS:

NC_000001.11:g.45331488C>T
NG_008189.1:g.13983G>A
NM_001048171.2:c.1171G>A
NM_001048172.2:c.1174G>A
NM_001048173.2:c.1171G>A
NM_001048174.2:c.1171G>AMANE SELECT
NM_001128425.2:c.1255G>A
NM_001293190.2:c.1216G>A
NM_001293191.2:c.1204G>A
NM_001293192.2:c.895G>A
NM_001293195.2:c.1171G>A
NM_001293196.2:c.895G>A
NM_001350650.2:c.826G>A
NM_001350651.2:c.826G>A
NM_012222.3:c.1246G>A
NP_001041636.1:p.Ala405Thr
NP_001041636.2:p.Ala391Thr
NP_001041637.1:p.Ala392Thr
NP_001041638.1:p.Ala391Thr
NP_001041639.1:p.Ala391Thr
NP_001121897.1:p.Ala419Thr
NP_001121897.1:p.Ala419Thr
NP_001280119.1:p.Ala406Thr
NP_001280120.1:p.Ala402Thr
NP_001280121.1:p.Ala299Thr
NP_001280124.1:p.Ala391Thr
NP_001280125.1:p.Ala299Thr
NP_001337579.1:p.Ala276Thr
NP_001337580.1:p.Ala276Thr
NP_036354.1:p.Ala416Thr
LRG_220t1:c.1255G>A
LRG_220:g.13983G>A
LRG_220p1:p.Ala419Thr
NC_000001.10:g.45797160C>T
NM_001048171.1:c.1213G>A
NM_001128425.1:c.1255G>A
NR_146882.2:n.1399G>A
NR_146883.2:n.1248G>A
p.A419T

Protein change:

A276T

Links:

dbSNP: rs587780744

NCBI 1000 Genomes Browser:

rs587780744

Molecular consequence:

NM_001048171.2:c.1171G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.1174G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.1171G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.1171G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.1255G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.1216G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.1204G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.895G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.1171G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.895G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.826G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.826G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.1246G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.1399G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.1248G>A - 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

Recent activity

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Mus musculus tribbles pseudokinase 3 (Trib3), mRNA
Mus musculus tribbles pseudokinase 3 (Trib3), mRNA
gi|117553620|ref|NM_175093.2|

Nucleotide
BP694335 Osada Taira anterior neuroectoderm (ANE) pCS105 cDNA library Xenopus la...
BP694335 Osada Taira anterior neuroectoderm (ANE) pCS105 cDNA library Xenopus laevis cDNA clone XL474d19ex 5', mRNA sequence
gi|46042290|gnl|dbEST|24560068|dbj| 335.1|

Nucleotide
AGENCOURT_12925778 NICHD_XGC_Te1 Xenopus laevis cDNA clone IMAGE:6930646 5', mRN...
AGENCOURT_12925778 NICHD_XGC_Te1 Xenopus laevis cDNA clone IMAGE:6930646 5', mRNA sequence
gi|29508975|gnl|dbEST|17327191|gb|C 19.1|

Nucleotide
Nmi N-myc (and STAT) interactor [Mus musculus]
Nmi N-myc (and STAT) interactor [Mus musculus]
Gene ID:64685

Gene
Nicotiana tabacum partial mRNA for Type II (MIKC) MADS-box transcription factor ...
Nicotiana tabacum partial mRNA for Type II (MIKC) MADS-box transcription factor (GLOBOSA gene), cultivar SR1, clone GLO3TA3
gi|605047835|emb|HG937779.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000185354	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Benign (May 7, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17161978, 17581577, 19725997, 25980754 Citation Link,
SCV000685557	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 7, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17581577, 25980754, 26689913, 25741868
SCV002532215	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Oct 8, 2021)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 25980754, 26689913, 33471991 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000185354

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Benign
(May 7, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000685557

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 7, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002532215

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Oct 8, 2021)

germline

curation

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

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, curation

Citations

PubMed

MUTYH-associated polyposis--from defect in base excision repair to clinical genetic testing.

Cheadle JP, Sampson JR.

DNA Repair (Amst). 2007 Mar 1;6(3):274-9. Epub 2006 Dec 11. Review.

PubMed [citation]

PMID:: 17161978

Base excision repair and the role of MUTYH.

Kairupan C, Scott RJ.

Hered Cancer Clin Pract. 2007 Dec 15;5(4):199-209. doi: 10.1186/1897-4287-5-4-199.

PubMed [citation]

PMID:: 19725997
PMCID:: PMC2736980

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000185354.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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, SCV000685557.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces alanine with threonine at codon 419 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 been reported in individuals affected with MUTYH-associated polyposis, colorectal cancer, glioblastoma, and suspected Lynch syndrome (PMID: 17581577, 25980754, 26689913, Insight-database.org), This variant has been identified in 19/282560 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

From Sema4, Sema4, SCV002532215.1

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

#	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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