NM_001048174.2(MUTYH):c.1504G>T (p.Asp502Tyr) AND Familial adenomatous polyposis 2

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Jan 23, 2025
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:: RCV000205460.22

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1504G>T (p.Asp502Tyr)]

NM_001048174.2(MUTYH):c.1504G>T (p.Asp502Tyr)

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.1504G>T (p.Asp502Tyr)

Other names:

p.D530Y:GAT>TAT

HGVS:

NC_000001.11:g.45329368C>A
NG_008189.1:g.16103G>T
NM_001048171.2:c.1504G>T
NM_001048172.2:c.1507G>T
NM_001048173.2:c.1504G>T
NM_001048174.2:c.1504G>TMANE SELECT
NM_001128425.2:c.1588G>T
NM_001293190.2:c.1549G>T
NM_001293191.2:c.1537G>T
NM_001293192.2:c.1228G>T
NM_001293195.2:c.1504G>T
NM_001293196.2:c.1228G>T
NM_001350650.2:c.1159G>T
NM_001350651.2:c.1159G>T
NM_012222.3:c.1579G>T
NP_001041636.2:p.Asp502Tyr
NP_001041637.1:p.Asp503Tyr
NP_001041638.1:p.Asp502Tyr
NP_001041639.1:p.Asp502Tyr
NP_001121897.1:p.Asp530Tyr
NP_001121897.1:p.Asp530Tyr
NP_001280119.1:p.Asp517Tyr
NP_001280120.1:p.Asp513Tyr
NP_001280121.1:p.Asp410Tyr
NP_001280124.1:p.Asp502Tyr
NP_001280125.1:p.Asp410Tyr
NP_001337579.1:p.Asp387Tyr
NP_001337580.1:p.Asp387Tyr
NP_036354.1:p.Asp527Tyr
LRG_220t1:c.1588G>T
LRG_220:g.16103G>T
LRG_220p1:p.Asp530Tyr
NC_000001.10:g.45795040C>A
NM_001128425.1:c.1588G>T
NR_146882.2:n.1912G>T
NR_146883.2:n.1761G>T

Protein change:

D387Y

Links:

dbSNP: rs147923905

NCBI 1000 Genomes Browser:

rs147923905

Molecular consequence:

NM_001048171.2:c.1504G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.1507G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.1504G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.1504G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.1588G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.1549G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.1537G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.1228G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.1504G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.1228G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.1159G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.1159G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.1579G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.1912G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.1761G>T - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000260471	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 23, 2025)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32255556, 34816434, 28492532
SCV003817134	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 28, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004198808	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 17, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004832049	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 7, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 29641532, 30267214, 32255556, 33471991, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	20	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

Monoallelic deleterious MUTYH germline variants as a driver for tumorigenesis.

Barreiro RAS, Sabbaga J, Rossi BM, Achatz MIW, Bettoni F, Camargo AA, Asprino PF, A F Galante P.

J Pathol. 2022 Feb;256(2):214-222. doi: 10.1002/path.5829. Epub 2021 Nov 23.

PubMed [citation]

PMID:: 34816434

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 (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000260471.13

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 530 of the MUTYH protein (p.Asp530Tyr). This variant is present in population databases (rs147923905, gnomAD 0.01%). This missense change has been observed in individual(s) with pancreatic cancer and/or lung cancer (PMID: 32255556, 34816434). ClinVar contains an entry for this variant (Variation ID: 182685). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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 Revvity Omics, Revvity, SCV003817134.2

#	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

From Baylor Genetics, SCV004198808.2

#	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

From All of Us Research Program, National Institutes of Health, SCV004832049.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	20	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces aspartic acid with tyrosine at codon 530 of the MUTYH protein. This variant is also known as c.1546G>T (p.Asp516Tyr) based on an alternative transcript (NM_001048171). 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 an individual affected with pancreatic ductal adenocarcinoma (PMID: 32255556), melanoma (PMID: 29641532), and breast cancer (PMID: 33471991), but also in unaffected controls (PMID: 30267214, 33471991). This variant has been identified in 19/282892 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		20	not provided	not provided	not provided

Last Updated: Apr 7, 2025

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