NM_001048174.2(MUTYH):c.210del (p.Ser71fs) AND Familial adenomatous polyposis 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 5, 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:: RCV001385505.7

Allele description [Variation Report for NM_001048174.2(MUTYH):c.210del (p.Ser71fs)]

NM_001048174.2(MUTYH):c.210del (p.Ser71fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

1p34.1

Genomic location:

Preferred name:

NM_001048174.2(MUTYH):c.210del (p.Ser71fs)

HGVS:

NC_000001.11:g.45333469del
NG_008189.1:g.12004del
NM_001048171.2:c.210del
NM_001048172.2:c.213del
NM_001048173.2:c.210del
NM_001048174.2:c.210delMANE SELECT
NM_001128425.2:c.294del
NM_001293190.2:c.255del
NM_001293191.2:c.243del
NM_001293192.2:c.-67del
NM_001293195.2:c.210del
NM_001293196.2:c.-67del
NM_001350650.2:c.-62del
NM_001350651.2:c.-62del
NM_012222.3:c.285del
NP_001041636.2:p.Ser71fs
NP_001041637.1:p.Ser72fs
NP_001041638.1:p.Ser71fs
NP_001041639.1:p.Ser71fs
NP_001121897.1:p.Ser99fs
NP_001280119.1:p.Ser86fs
NP_001280120.1:p.Ser82fs
NP_001280124.1:p.Ser71fs
NP_036354.1:p.Ser96fs
LRG_220t1:c.294del
LRG_220:g.12004del
NC_000001.10:g.45799139del
NC_000001.10:g.45799141del
NM_001128425.1:c.294del
NM_001128425.1:c.294delG
NR_146882.2:n.438del
NR_146883.2:n.361del

Protein change:

S71fs

Links:

dbSNP: rs1557486313

NCBI 1000 Genomes Browser:

rs1557486313

Molecular consequence:

NM_001293192.2:c.-67del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001293196.2:c.-67del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350650.2:c.-62del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350651.2:c.-62del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001048171.2:c.210del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001048172.2:c.213del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001048173.2:c.210del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001048174.2:c.210del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001128425.2:c.294del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001293190.2:c.255del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001293191.2:c.243del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001293195.2:c.210del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_012222.3:c.285del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_146882.2:n.438del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.361del - 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
SCV001585383	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 15, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18534194, 20663686, 12606733, 28492532
SCV004837953	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 5, 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

SCV001585383

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 15, 2020)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004837953

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 5, 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

Characterization of mutant MUTYH proteins associated with familial colorectal cancer.

Ali M, Kim H, Cleary S, Cupples C, Gallinger S, Bristow R.

Gastroenterology. 2008 Aug;135(2):499-507. doi: 10.1053/j.gastro.2008.04.035. Epub 2008 May 7.

PubMed [citation]

PMID:: 18534194
PMCID:: PMC2761659

MUTYH-associated polyposis (MAP).

Nielsen M, Morreau H, Vasen HF, Hes FJ.

Crit Rev Oncol Hematol. 2011 Jul;79(1):1-16. doi: 10.1016/j.critrevonc.2010.05.011. Epub 2010 Jul 21. Review.

PubMed [citation]

PMID:: 20663686

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV001585383.4

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

Description

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). This variant has been observed in individual(s) with polyposis and colorectal cancer (PMID: 12606733). This variant is also known as 252delG in the literature. ClinVar contains an entry for this variant (Variation ID: 631361). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser99Alafs*3) in the MUTYH gene. It is expected to result in an absent or disrupted protein product.

#	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, SCV004837953.1

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

Description

This variant deletes 1 nucleotide in exon 3 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

#	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: Apr 20, 2024

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