NM_001048174.2(MUTYH):c.409G>A (p.Ala137Thr) AND Familial adenomatous polyposis 2

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Mar 19, 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:: RCV000228243.15

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]

Observations:

Condition(s)

Name:: Familial adenomatous polyposis 2
Synonyms:: COLORECTAL ADENOMATOUS POLYPOSIS, AUTOSOMAL RECESSIVE; ADENOMAS, MULTIPLE COLORECTAL, AUTOSOMAL RECESSIVE; MYH-associated polyposis; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012041; MedGen: C3272841; Orphanet: 220460; OMIM: 608456

Recent activity

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Solute carrier family 25, member 28 [Mus musculus]
Solute carrier family 25, member 28 [Mus musculus]
gi|19483946|gb|AAH25908.1|

Protein
POMGNT1 protein O-linked mannose N-acetylglucosaminyltransferase 1 (beta 1,2-) [...
POMGNT1 protein O-linked mannose N-acetylglucosaminyltransferase 1 (beta 1,2-) [Bos taurus]
Gene ID:506551

Gene
uncultured Blautia sp. isolate 2789STDY5608880 genome assembly, contig: SCcontig...
uncultured Blautia sp. isolate 2789STDY5608880 genome assembly, contig: SCcontig000009, whole genome shotgun sequence
gi|1052882413|emb|FMEU01000009.1|

Nucleotide
uncultured Blautia sp. isolate 2789STDY5608848 genome assembly, contig: SCcontig...
uncultured Blautia sp. isolate 2789STDY5608848 genome assembly, contig: SCcontig000006, whole genome shotgun sequence
gi|1052899138|emb|FMFK01000006.1|

Nucleotide
uncultured Blautia sp. isolate 2789STDY5608880 genome assembly, contig: SCcontig...
uncultured Blautia sp. isolate 2789STDY5608880 genome assembly, contig: SCcontig000005, whole genome shotgun sequence
gi|1052883023|emb|FMEU01000005.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000285952	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 27, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31159747, 28492532
SCV000792228	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Jun 13, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26689913, 25186627 Citation Link,
SCV004839716	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25186627, 26689913, 33471991, 25741868
SCV005056031	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 19, 2024)	unknown	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	3	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.

Tsaousis GN, Papadopoulou E, Apessos A, Agiannitopoulos K, Pepe G, Kampouri S, Diamantopoulos N, Floros T, Iosifidou R, Katopodi O, Koumarianou A, Markopoulos C, Papazisis K, Venizelos V, Xanthakis I, Xepapadakis G, Banu E, Eniu DT, Negru S, Stanculeanu DL, Ungureanu A, Ozmen V, et al.

BMC Cancer. 2019 Jun 3;19(1):535. doi: 10.1186/s12885-019-5756-4.

PubMed [citation]

PMID:: 31159747
PMCID:: PMC6547505

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000285952.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 165 of the MUTYH protein (p.Ala165Thr). This variant is present in population databases (rs201103359, gnomAD 0.03%). This missense change has been observed in individual(s) with MUTYH-related conditions (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 185959). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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 Counsyl, SCV000792228.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

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

From All of Us Research Program, National Institutes of Health, SCV004839716.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	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	108544	not provided	not provided		3	not provided	not provided	not provided

From Baylor Genetics, SCV005056031.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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