NM_001048174.2(MUTYH):c.602G>A (p.Gly201Asp) AND Familial adenomatous polyposis 2

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Oct 7, 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:: RCV000554982.14

Allele description [Variation Report for NM_001048174.2(MUTYH):c.602G>A (p.Gly201Asp)]

NM_001048174.2(MUTYH):c.602G>A (p.Gly201Asp)

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.602G>A (p.Gly201Asp)

HGVS:

NC_000001.11:g.45332578C>T
NG_008189.1:g.12893G>A
NM_001048171.2:c.602G>A
NM_001048172.2:c.605G>A
NM_001048173.2:c.602G>A
NM_001048174.2:c.602G>AMANE SELECT
NM_001128425.2:c.686G>A
NM_001293190.2:c.647G>A
NM_001293191.2:c.635G>A
NM_001293192.2:c.326G>A
NM_001293195.2:c.602G>A
NM_001293196.2:c.326G>A
NM_001350650.2:c.257G>A
NM_001350651.2:c.257G>A
NM_012222.3:c.677G>A
NP_001041636.2:p.Gly201Asp
NP_001041637.1:p.Gly202Asp
NP_001041638.1:p.Gly201Asp
NP_001041639.1:p.Gly201Asp
NP_001121897.1:p.Gly229Asp
NP_001121897.1:p.Gly229Asp
NP_001280119.1:p.Gly216Asp
NP_001280120.1:p.Gly212Asp
NP_001280121.1:p.Gly109Asp
NP_001280124.1:p.Gly201Asp
NP_001280125.1:p.Gly109Asp
NP_001337579.1:p.Gly86Asp
NP_001337580.1:p.Gly86Asp
NP_036354.1:p.Gly226Asp
LRG_220t1:c.686G>A
LRG_220:g.12893G>A
LRG_220p1:p.Gly229Asp
NC_000001.10:g.45798250C>T
NM_001128425.1:c.686G>A
NR_146882.2:n.830G>A
NR_146883.2:n.679G>A
p.G229D

Protein change:

G109D

Links:

dbSNP: rs752114814

NCBI 1000 Genomes Browser:

rs752114814

Molecular consequence:

NM_001048171.2:c.602G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.605G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.602G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.602G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.686G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.647G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.635G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.602G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.257G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.257G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.677G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.830G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.679G>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000639351	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 7, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004198915	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 2, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004841526	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Sep 4, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000639351

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 7, 2023)

germline

clinical testing

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

SCV004198915

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 2, 2023)

unknown

clinical testing

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

SCV004841526

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Sep 4, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	4	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

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

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000639351.9

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 229 of the MUTYH protein (p.Gly229Asp). This variant is present in population databases (rs752114814, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 186889). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 Baylor Genetics, SCV004198915.1

#	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

From All of Us Research Program, National Institutes of Health, SCV004841526.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces glycine with aspartic acid at codon 229 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large international case-control study, this variant was reported in 3/60466 breast cancer cases and 3/53461 controls (PMID: 33471991). This variant has been identified in 5/251340 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		4	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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