NM_001048174.2(MUTYH):c.1556del (p.Ala519fs) AND Familial adenomatous polyposis 2

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Oct 15, 2023
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:: RCV000200142.13

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1556del (p.Ala519fs)]

NM_001048174.2(MUTYH):c.1556del (p.Ala519fs)

Gene:

MUTYH:mutY DNA glycosylase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

1p34.1

Genomic location:

Preferred name:

NM_001048174.2(MUTYH):c.1556del (p.Ala519fs)

HGVS:

NC_000001.11:g.45329316del
NG_008189.1:g.16155del
NM_001048171.2:c.1556del
NM_001048172.2:c.1559del
NM_001048173.2:c.1556del
NM_001048174.2:c.1556delMANE SELECT
NM_001128425.2:c.1640del
NM_001293190.2:c.1601del
NM_001293191.2:c.1589del
NM_001293192.2:c.1280del
NM_001293195.2:c.1556del
NM_001293196.2:c.1280del
NM_001350650.2:c.1211del
NM_001350651.2:c.1211del
NM_012222.3:c.1631del
NP_001041636.2:p.Ala519fs
NP_001041637.1:p.Ala520fs
NP_001041638.1:p.Ala519fs
NP_001041639.1:p.Ala519fs
NP_001121897.1:p.Ala547fs
NP_001121897.1:p.Ala547fs
NP_001280119.1:p.Ala534fs
NP_001280120.1:p.Ala530fs
NP_001280121.1:p.Ala427fs
NP_001280124.1:p.Ala519fs
NP_001280125.1:p.Ala427fs
NP_001337579.1:p.Ala404fs
NP_001337580.1:p.Ala404fs
NP_036354.1:p.Ala544fs
LRG_220t1:c.1640del
LRG_220:g.16155del
LRG_220p1:p.Ala547fs
NC_000001.10:g.45794988del
NM_001048171.1:c.1598delC
NM_001128425.1:c.1640del
NM_001128425.1:c.1640delC
NR_146882.2:n.1964del
NR_146883.2:n.1813del
p.A547EfsX24

Protein change:

A404fs

Links:

dbSNP: rs587780086

NCBI 1000 Genomes Browser:

rs587780086

Molecular consequence:

NM_001048171.2:c.1556del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001048172.2:c.1559del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001048173.2:c.1556del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001048174.2:c.1556del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001128425.2:c.1640del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001293190.2:c.1601del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001293191.2:c.1589del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001293192.2:c.1280del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001293195.2:c.1556del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001293196.2:c.1280del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001350650.2:c.1211del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001350651.2:c.1211del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_012222.3:c.1631del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_146882.2:n.1964del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.1813del - 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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LOC108485743 [Gossypium arboreum]
LOC108485743 [Gossypium arboreum]
Gene ID:108485743

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000253864	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 15, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34704405, 28492532
SCV000487313	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Uncertain significance (Nov 20, 2015)	unknown	clinical testing	mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV004198919	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 26, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004827713	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Aug 15, 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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Filling the gap: A thorough investigation for the genetic diagnosis of unsolved polyposis patients with monoallelic MUTYH pathogenic variants.

Dell'Elice A, Cini G, Fornasarig M, Armelao F, Barana D, Bianchi F, Casalis Cavalchini GC, Maffè A, Mammi I, Pedroni M, Percesepe A, Sorrentini I, Tibiletti M, Maestro R, Quaia M, Viel A.

Mol Genet Genomic Med. 2021 Dec;9(12):e1831. doi: 10.1002/mgg3.1831. Epub 2021 Oct 26.

PubMed [citation]

PMID:: 34704405
PMCID:: PMC8683633

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, SCV000253864.8

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

Description

This sequence change results in a frameshift in the MUTYH gene (p.Ala547Glufs*24). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3 amino acid(s) of the MUTYH protein and extend the protein by 20 additional amino acid residues. This variant is present in population databases (rs587780086, gnomAD 0.004%). This frameshift has been observed in individual(s) with MUTYH-associated polyposis (PMID: 34704405; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 127843). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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, SCV000487313.2

#	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 Baylor Genetics, SCV004198919.1

#	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, SCV004827713.1

#	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	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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