NM_001048174.2(MUTYH):c.409G>A (p.Ala137Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Apr 17, 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:: RCV000165474.17

Allele description [Variation Report for NM_001048174.2(MUTYH):c.409G>A (p.Ala137Thr)]

NM_001048174.2(MUTYH):c.409G>A (p.Ala137Thr)

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.409G>A (p.Ala137Thr)

HGVS:

NC_000001.11:g.45332929C>T
NG_008189.1:g.12542G>A
NM_001048171.2:c.409G>A
NM_001048172.2:c.412G>A
NM_001048173.2:c.409G>A
NM_001048174.2:c.409G>AMANE SELECT
NM_001128425.2:c.493G>A
NM_001293190.2:c.454G>A
NM_001293191.2:c.442G>A
NM_001293192.2:c.133G>A
NM_001293195.2:c.409G>A
NM_001293196.2:c.133G>A
NM_001350650.2:c.64G>A
NM_001350651.2:c.64G>A
NM_012222.3:c.484G>A
NP_001041636.1:p.Ala151Thr
NP_001041636.2:p.Ala137Thr
NP_001041637.1:p.Ala138Thr
NP_001041638.1:p.Ala137Thr
NP_001041639.1:p.Ala137Thr
NP_001121897.1:p.Ala165Thr
NP_001121897.1:p.Ala165Thr
NP_001280119.1:p.Ala152Thr
NP_001280120.1:p.Ala148Thr
NP_001280121.1:p.Ala45Thr
NP_001280124.1:p.Ala137Thr
NP_001280125.1:p.Ala45Thr
NP_001337579.1:p.Ala22Thr
NP_001337580.1:p.Ala22Thr
NP_036354.1:p.Ala162Thr
LRG_220t1:c.493G>A
LRG_220:g.12542G>A
LRG_220p1:p.Ala165Thr
NC_000001.10:g.45798601C>T
NM_001048171.1:c.451G>A
NM_001128425.1:c.493G>A
NR_146882.2:n.637G>A
NR_146883.2:n.486G>A
p.A165T

Protein change:

A137T

Links:

dbSNP: rs201103359

NCBI 1000 Genomes Browser:

rs201103359

Molecular consequence:

NM_001048171.2:c.409G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.412G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.409G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.409G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.493G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.454G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.442G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.133G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.409G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.133G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.64G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.64G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.484G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.637G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.486G>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

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ankyrin repeat and SAM domain-containing protein 1A [Homo sapiens]
ankyrin repeat and SAM domain-containing protein 1A [Homo sapiens]
gi|140161500|ref|NP_056060.2|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000216205	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 8, 2023)	germline	clinical testing	Citation Link,
SCV000685633	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 17, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25186627, 26689913, 33471991, 25741868
SCV000822074	GeneKor MSA	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 1, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002532294	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Feb 10, 2022)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 29212164, 26689913, 25186627, 33471991, 30982232 Citation Link,
SCV004014955	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort.

Raskin L, Guo Y, Du L, Clendenning M, Rosty C; Colon Cancer Family Registry (CCFR)., Lindor NM, Gruber SB, Buchanan DD.

Oncotarget. 2017 Nov 7;8(55):93450-93463. doi: 10.18632/oncotarget.18596.

PubMed [citation]

PMID:: 29212164
PMCID:: PMC5706810

Patterns and functional implications of rare germline variants across 12 cancer types.

Lu C, Xie M, Wendl MC, Wang J, McLellan MD, Leiserson MD, Huang KL, Wyczalkowski MA, Jayasinghe R, Banerjee T, Ning J, Tripathi P, Zhang Q, Niu B, Ye K, Schmidt HK, Fulton RS, McMichael JF, Batra P, Kandoth C, Bharadwaj M, Koboldt DC, et al.

Nat Commun. 2015 Dec 22;6:10086. doi: 10.1038/ncomms10086.

PubMed [citation]

PMID:: 26689913
PMCID:: PMC4703835

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000216205.8

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

Description

The p.A165T variant (also known as c.493G>A), located in coding exon 6 of the MUTYH gene, results from a G to A substitution at nucleotide position 493. The alanine at codon 165 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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, SCV000685633.5

#	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 165 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer and kidney renal clear cell carcinoma (PMID: 25186627, 26689913, 33471991). This variant has been detected in a breast cancer case-control meta-analysis in 4/60466 breast cancer cases and 11/53461 controls (PMID: 33471991). This variant has also been identified in 12/281892 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 GeneKor MSA, SCV000822074.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002532294.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (5)

#	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 Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C., SCV004014955.1

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

#	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 20, 2024

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