NM_001048174.2(MUTYH):c.1226G>T (p.Arg409Leu) AND Familial adenomatous polyposis 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 27, 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:: RCV001857463.6

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1226G>T (p.Arg409Leu)]

NM_001048174.2(MUTYH):c.1226G>T (p.Arg409Leu)

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.1226G>T (p.Arg409Leu)

HGVS:

NC_000001.11:g.45331433C>A
NG_008189.1:g.14038G>T
NM_001048171.2:c.1226G>T
NM_001048172.2:c.1229G>T
NM_001048173.2:c.1226G>T
NM_001048174.2:c.1226G>TMANE SELECT
NM_001128425.2:c.1310G>T
NM_001293190.2:c.1271G>T
NM_001293191.2:c.1259G>T
NM_001293192.2:c.950G>T
NM_001293195.2:c.1226G>T
NM_001293196.2:c.950G>T
NM_001350650.2:c.881G>T
NM_001350651.2:c.881G>T
NM_012222.3:c.1301G>T
NP_001041636.2:p.Arg409Leu
NP_001041637.1:p.Arg410Leu
NP_001041638.1:p.Arg409Leu
NP_001041639.1:p.Arg409Leu
NP_001121897.1:p.Arg437Leu
NP_001121897.1:p.Arg437Leu
NP_001280119.1:p.Arg424Leu
NP_001280120.1:p.Arg420Leu
NP_001280121.1:p.Arg317Leu
NP_001280124.1:p.Arg409Leu
NP_001280125.1:p.Arg317Leu
NP_001337579.1:p.Arg294Leu
NP_001337580.1:p.Arg294Leu
NP_036354.1:p.Arg434Leu
LRG_220t1:c.1310G>T
LRG_220:g.14038G>T
LRG_220p1:p.Arg437Leu
NC_000001.10:g.45797105C>A
NM_001128425.1:c.1310G>T
NR_146882.2:n.1454G>T
NR_146883.2:n.1303G>T
p.R437L

Protein change:

R294L

Links:

dbSNP: rs587782120

NCBI 1000 Genomes Browser:

rs587782120

Molecular consequence:

NM_001048171.2:c.1226G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.1229G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.1226G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.1226G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.1310G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.1271G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.1259G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.950G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.1226G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.950G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.881G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.881G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.1301G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.1454G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.1303G>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
SCV002177062	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 27, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004828636	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Apr 3, 2023)	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

SCV002177062

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 27, 2023)

germline

clinical testing

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

SCV004828636

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Apr 3, 2023)

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

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Invitae, SCV002177062.3

#	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 arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 437 of the MUTYH protein (p.Arg437Leu). This variant is present in population databases (rs587782120, gnomAD 0.006%). 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: 142471). 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 All of Us Research Program, National Institutes of Health, SCV004828636.1

#	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 leucine at codon 437 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 MUTYH-related disorders in the literature. This variant has been identified in 2/251368 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: Jun 23, 2024

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