NM_001048174.2(MUTYH):c.14G>A (p.Arg5Gln) AND Familial adenomatous polyposis 2

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Feb 6, 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:: RCV000230254.16

Allele description [Variation Report for NM_001048174.2(MUTYH):c.14G>A (p.Arg5Gln)]

NM_001048174.2(MUTYH):c.14G>A (p.Arg5Gln)

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.14G>A (p.Arg5Gln)

Other names:

p.R19Q:CGA>CAA

HGVS:

NC_000001.11:g.45334492C>T
NG_008189.1:g.10979G>A
NM_001048171.2:c.14G>A
NM_001048172.2:c.14G>A
NM_001048173.2:c.14G>A
NM_001048174.2:c.14G>AMANE SELECT
NM_001128425.2:c.56G>A
NM_001293190.2:c.56G>A
NM_001293191.2:c.14G>A
NM_001293192.2:c.-199G>A
NM_001293195.2:c.14G>A
NM_001293196.2:c.-199G>A
NM_001350650.2:c.-258G>A
NM_001350651.2:c.-194G>A
NM_012222.3:c.56G>A
NP_001041636.1:p.Arg19Gln
NP_001041636.2:p.Arg5Gln
NP_001041637.1:p.Arg5Gln
NP_001041638.1:p.Arg5Gln
NP_001041639.1:p.Arg5Gln
NP_001121897.1:p.Arg19Gln
NP_001121897.1:p.Arg19Gln
NP_001280119.1:p.Arg19Gln
NP_001280120.1:p.Arg5Gln
NP_001280124.1:p.Arg5Gln
NP_036354.1:p.Arg19Gln
LRG_220t1:c.56G>A
LRG_220:g.10979G>A
LRG_220p1:p.Arg19Gln
NC_000001.10:g.45800164C>T
NM_001048171.1:c.56G>A
NM_001128425.1:c.56G>A
NR_146882.2:n.242G>A
NR_146883.2:n.165G>A
p.R19Q

Protein change:

R19Q

Links:

dbSNP: rs587780081

NCBI 1000 Genomes Browser:

rs587780081

Molecular consequence:

NM_001293192.2:c.-199G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001293196.2:c.-199G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350650.2:c.-258G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350651.2:c.-194G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001048171.2:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.56G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.56G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.56G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.242G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.165G>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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LOC127423795 [Myxocyprinus asiaticus]
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000285958	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 16, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21777424, 22297469, 25980754, 34326862, 28492532
SCV000790004	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Mar 14, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21777424, 25980754, 22297469 Citation Link,
SCV000837785	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV004835726	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] 21777424, 22297469, 25980754, 25741868
SCV005056053	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 6, 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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	13	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach.

Bhai P, Levy MA, Rooney K, Carere DA, Reilly J, Kerkhof J, Volodarsky M, Stuart A, Kadour M, Panabaker K, Schenkel LC, Lin H, Ainsworth P, Sadikovic B.

Front Genet. 2021;12:698595. doi: 10.3389/fgene.2021.698595.

PubMed [citation]

PMID:: 34326862
PMCID:: PMC8314385

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, SCV000285958.10

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

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 19 of the MUTYH protein (p.Arg19Gln). This variant is present in population databases (rs587780081, gnomAD 0.005%). This missense change has been observed in individual(s) with breast cancer, suspected of Lynch syndrome and undergoing MUTYH-associated polyposis testing (PMID: 21777424, 22297469, 25980754, 34326862). ClinVar contains an entry for this variant (Variation ID: 127834). 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 glutamine 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 Counsyl, SCV000790004.1

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

#	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 Mendelics, SCV000837785.2

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

#	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, SCV004835726.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	13	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces arginine with glutamine 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 been reported in two individuals affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754, 21777424) and in an individual affected with breast cancer (PMID: 22297469). This variant has been identified in 7/251490 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		13	not provided	not provided	not provided

From Baylor Genetics, SCV005056053.1

#	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: Sep 29, 2024

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