NM_001048174.2(MUTYH):c.631G>A (p.Val211Ile) AND Familial adenomatous polyposis 2

Germline classification:: Uncertain significance (6 submissions)
Last evaluated:: Dec 18, 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:: RCV000409405.20

Allele description [Variation Report for NM_001048174.2(MUTYH):c.631G>A (p.Val211Ile)]

NM_001048174.2(MUTYH):c.631G>A (p.Val211Ile)

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.631G>A (p.Val211Ile)

Other names:

p.Val239Ile

HGVS:

NC_000001.11:g.45332464C>T
NG_008189.1:g.13007G>A
NM_001048171.2:c.631G>A
NM_001048172.2:c.634G>A
NM_001048173.2:c.631G>A
NM_001048174.2:c.631G>AMANE SELECT
NM_001128425.2:c.715G>A
NM_001293190.2:c.676G>A
NM_001293191.2:c.664G>A
NM_001293192.2:c.355G>A
NM_001293195.2:c.631G>A
NM_001293196.2:c.355G>A
NM_001350650.2:c.286G>A
NM_001350651.2:c.286G>A
NM_012222.3:c.706G>A
NP_001041636.1:p.Val225Ile
NP_001041636.2:p.Val211Ile
NP_001041637.1:p.Val212Ile
NP_001041638.1:p.Val211Ile
NP_001041639.1:p.Val211Ile
NP_001121897.1:p.Val239Ile
NP_001121897.1:p.Val239Ile
NP_001280119.1:p.Val226Ile
NP_001280120.1:p.Val222Ile
NP_001280121.1:p.Val119Ile
NP_001280124.1:p.Val211Ile
NP_001280125.1:p.Val119Ile
NP_001337579.1:p.Val96Ile
NP_001337580.1:p.Val96Ile
NP_036354.1:p.Val236Ile
LRG_220t1:c.715G>A
LRG_220:g.13007G>A
LRG_220p1:p.Val239Ile
NC_000001.10:g.45798136C>T
NM_001048171.1:c.673G>A
NM_001128425.1:c.715G>A
NR_146882.2:n.859G>A
NR_146883.2:n.708G>A
p.V239I

Protein change:

V119I

Links:

dbSNP: rs759295912

NCBI 1000 Genomes Browser:

rs759295912

Molecular consequence:

NM_001048171.2:c.631G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.634G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.631G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.631G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.715G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.676G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.664G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.355G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.631G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.355G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.286G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.286G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.706G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.859G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.708G>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
SCV000487346	Counsyl	no assertion criteria provided	Uncertain significance (Apr 13, 2016)	unknown	clinical testing
SCV000639353	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 18, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28961279, 32068069, 28492532
SCV001135257	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001749576	GenomeConnect - Invitae Patient Insights Network	no classification provided	not provided	unknown	phenotyping only
SCV004198831	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 15, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004841426	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 13, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28961279, 32068069, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	4	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, phenotyping only

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

The frequency of cancer predisposition gene mutations in hereditary breast and ovarian cancer patients in Taiwan: From BRCA1/2 to multi-gene panels.

Sung PL, Wen KC, Chen YJ, Chao TC, Tsai YF, Tseng LM, Qiu JT, Chao KC, Wu HH, Chuang CM, Wang PH, Huang CF.

PLoS One. 2017;12(9):e0185615. doi: 10.1371/journal.pone.0185615.

PubMed [citation]

PMID:: 28961279
PMCID:: PMC5621677

See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000487346.3

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

Description

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000639353.9

#	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 valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 239 of the MUTYH protein (p.Val239Ile). This variant is present in population databases (rs759295912, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 28961279, 32068069). This variant is also known as p.Val225Ile. ClinVar contains an entry for this variant (Variation ID: 187628). 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 tolerated. 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 Mendelics, SCV001135257.1

#	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 GenomeConnect - Invitae Patient Insights Network, SCV001749576.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

Variant interpreted as Uncertain significance and reported on 09-11-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

#	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 Baylor Genetics, SCV004198831.1

#	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, SCV004841426.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces valine with isoleucine at codon 239 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 individuals affected with breast cancer (PMID: 28961279, 32068069). This variant has been identified in 8/281912 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: Jun 29, 2025

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