NM_001048174.2(MUTYH):c.13C>G (p.Arg5Gly) AND Familial adenomatous polyposis 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 11, 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:: RCV000467752.9

Allele description [Variation Report for NM_001048174.2(MUTYH):c.13C>G (p.Arg5Gly)]

NM_001048174.2(MUTYH):c.13C>G (p.Arg5Gly)

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.13C>G (p.Arg5Gly)

HGVS:

NC_000001.11:g.45334493G>C
NG_008189.1:g.10978C>G
NM_001048171.2:c.13C>G
NM_001048172.2:c.13C>G
NM_001048173.2:c.13C>G
NM_001048174.2:c.13C>GMANE SELECT
NM_001128425.2:c.55C>G
NM_001293190.2:c.55C>G
NM_001293191.2:c.13C>G
NM_001293192.2:c.-200C>G
NM_001293195.2:c.13C>G
NM_001293196.2:c.-200C>G
NM_001350650.2:c.-259C>G
NM_001350651.2:c.-195C>G
NM_012222.3:c.55C>G
NP_001041636.2:p.Arg5Gly
NP_001041637.1:p.Arg5Gly
NP_001041638.1:p.Arg5Gly
NP_001041639.1:p.Arg5Gly
NP_001121897.1:p.Arg19Gly
NP_001121897.1:p.Arg19Gly
NP_001280119.1:p.Arg19Gly
NP_001280120.1:p.Arg5Gly
NP_001280124.1:p.Arg5Gly
NP_036354.1:p.Arg19Gly
LRG_220t1:c.55C>G
LRG_220:g.10978C>G
LRG_220p1:p.Arg19Gly
NC_000001.10:g.45800165G>C
NM_001128425.1:c.55C>G
NR_146882.2:n.241C>G
NR_146883.2:n.164C>G

Protein change:

R19G

Links:

dbSNP: rs587780088

NCBI 1000 Genomes Browser:

rs587780088

Molecular consequence:

NM_001293192.2:c.-200C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001293196.2:c.-200C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350650.2:c.-259C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350651.2:c.-195C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001048171.2:c.13C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.13C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.13C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.13C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.55C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.55C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.13C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.13C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.55C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.241C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.164C>G - 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
SCV000545727	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 20, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24470512, 28492532
SCV004835748	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 (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000545727

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 20, 2022)

germline

clinical testing

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

SCV004835748

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 (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	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Prevalence and characteristics of MUTYH-associated polyposis in patients with multiple adenomatous and serrated polyps.

Guarinos C, Juárez M, Egoavil C, Rodríguez-Soler M, Pérez-Carbonell L, Salas R, Cubiella J, Rodríguez-Moranta F, de-Castro L, Bujanda L, Serradesanferm A, Nicolás-Pérez D, Herráiz M, Fernández-Bañares F, Herreros-de-Tejada A, Aguirre E, Balmaña J, Rincón ML, Pizarro A, Polo-Ortiz F, Castillejo A, Alenda C, et al.

Clin Cancer Res. 2014 Mar 1;20(5):1158-68. doi: 10.1158/1078-0432.CCR-13-1490. Epub 2014 Jan 27.

PubMed [citation]

PMID:: 24470512

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 (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000545727.5

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

Description

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 406831). This missense change has been observed in individual(s) with colorectal polyposis (PMID: 24470512). This variant is present in population databases (rs587780088, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 19 of the MUTYH protein (p.Arg19Gly).

#	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 All of Us Research Program, National Institutes of Health, SCV004835748.1

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

Description

This missense variant replaces arginine with glycine at codon 19 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251478 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		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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