NM_001048174.2(MUTYH):c.1192C>T (p.Arg398Cys) AND Familial adenomatous polyposis 2

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Feb 1, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000119122.34

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1192C>T (p.Arg398Cys)]

NM_001048174.2(MUTYH):c.1192C>T (p.Arg398Cys)

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.1192C>T (p.Arg398Cys)

Other names:

p.R426C:CGT>TGT

HGVS:

NC_000001.11:g.45331467G>A
NG_008189.1:g.14004C>T
NM_001048171.2:c.1192C>T
NM_001048172.2:c.1195C>T
NM_001048173.2:c.1192C>T
NM_001048174.2:c.1192C>TMANE SELECT
NM_001128425.2:c.1276C>T
NM_001293190.2:c.1237C>T
NM_001293191.2:c.1225C>T
NM_001293192.2:c.916C>T
NM_001293195.2:c.1192C>T
NM_001293196.2:c.916C>T
NM_001350650.2:c.847C>T
NM_001350651.2:c.847C>T
NM_012222.3:c.1267C>T
NP_001041636.1:p.Arg412Cys
NP_001041636.2:p.Arg398Cys
NP_001041637.1:p.Arg399Cys
NP_001041638.1:p.Arg398Cys
NP_001041639.1:p.Arg398Cys
NP_001121897.1:p.Arg426Cys
NP_001121897.1:p.Arg426Cys
NP_001280119.1:p.Arg413Cys
NP_001280120.1:p.Arg409Cys
NP_001280121.1:p.Arg306Cys
NP_001280124.1:p.Arg398Cys
NP_001280125.1:p.Arg306Cys
NP_001337579.1:p.Arg283Cys
NP_001337580.1:p.Arg283Cys
NP_036354.1:p.Arg423Cys
NP_036354.1:p.Arg423Cys
LRG_220t1:c.1276C>T
LRG_220:g.14004C>T
LRG_220p1:p.Arg426Cys
NC_000001.10:g.45797139G>A
NM_001048171.1:c.1234C>T
NM_001048174.1:c.1192C>T
NM_001048174.2:c.1192C>T
NM_001128425.1:c.1276C>T
NM_012222.2:c.1267C>T
NR_146882.2:n.1420C>T
NR_146883.2:n.1269C>T
p.R426C

Protein change:

R283C

Links:

dbSNP: rs150792276

NCBI 1000 Genomes Browser:

rs150792276

Molecular consequence:

NM_001048171.2:c.1192C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.1195C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.1192C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.1192C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.1276C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.1237C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.1225C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.916C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.1192C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.916C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.847C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.847C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.1267C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.1420C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.1269C>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
SCV000153836	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Feb 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001253576	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	Citation Link,
SCV002580500	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 25, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003928044	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Uncertain significance (Jun 2, 2023)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	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, SCV000153836.14

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001253576.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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 MGZ Medical Genetics Center, SCV002580500.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV003928044.1

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

Description

The MUTYH c.1276C>T (p.Arg426Cys) missense change has a maximum subpopulation frequency of 0.15% in gnomAD v2.1.1 and is reported to be homozygous in one individual (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, however a functional assay in E.coli showed that glycosylase repair activity was comparable to the wildtype (PMID: 25820570). This variant has been reported as homozygous in individuals with familial adenomatous polyposis that reportedly did not harbor pathogenic variants in APC (PMID: 16134147, 16557584, 19531215, 20687945). It has also been reported to co-occur with a pathogenic MUYTH pathogenic variant in two individuals with ≥10 adenomas, where one of these individuals also had a personal and family history of colorectal cancer (PMID: 20687945). In addition, this variant has been reported as heterozygous in individuals with familial adenomatous polyposis (PMID: 17524638, 20687945, 22976915, 24470512), colorectal cancer (PMID: 28135145, 28944238, 30256826, 30850667), breast cancer (PMID: 26976419, 30564557), pancreatic cancer (PMID: 30151275), and endometrial cancer (PMID: 27443514). This variant is also known as p.Arg412Cys in the literature. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as 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

Last Updated: Aug 25, 2024

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