NM_001048174.2(MUTYH):c.559G>A (p.Val187Met) AND Familial adenomatous polyposis 2

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 29, 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:: RCV000502295.16

Allele description [Variation Report for NM_001048174.2(MUTYH):c.559G>A (p.Val187Met)]

NM_001048174.2(MUTYH):c.559G>A (p.Val187Met)

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.559G>A (p.Val187Met)

HGVS:

NC_000001.11:g.45332621C>T
NG_008189.1:g.12850G>A
NM_001048171.2:c.559G>A
NM_001048172.2:c.562G>A
NM_001048173.2:c.559G>A
NM_001048174.2:c.559G>AMANE SELECT
NM_001128425.2:c.643G>A
NM_001293190.2:c.604G>A
NM_001293191.2:c.592G>A
NM_001293192.2:c.283G>A
NM_001293195.2:c.559G>A
NM_001293196.2:c.283G>A
NM_001350650.2:c.214G>A
NM_001350651.2:c.214G>A
NM_012222.3:c.634G>A
NP_001041636.2:p.Val187Met
NP_001041637.1:p.Val188Met
NP_001041638.1:p.Val187Met
NP_001041639.1:p.Val187Met
NP_001121897.1:p.Val215Met
NP_001121897.1:p.Val215Met
NP_001280119.1:p.Val202Met
NP_001280120.1:p.Val198Met
NP_001280121.1:p.Val95Met
NP_001280124.1:p.Val187Met
NP_001280125.1:p.Val95Met
NP_001337579.1:p.Val72Met
NP_001337580.1:p.Val72Met
NP_036354.1:p.Val212Met
LRG_220t1:c.643G>A
LRG_220:g.12850G>A
LRG_220p1:p.Val215Met
NC_000001.10:g.45798293C>T
NM_001128425.1:c.643G>A
NR_146882.2:n.787G>A
NR_146883.2:n.636G>A
p.V215M

Protein change:

V187M

Links:

dbSNP: rs776487884

NCBI 1000 Genomes Browser:

rs776487884

Molecular consequence:

NM_001048171.2:c.559G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.562G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.559G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.559G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.643G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.604G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.592G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.283G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.559G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.283G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.214G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.214G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.634G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.787G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.636G>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
SCV000639349	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 29, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19032956, 19732775, 20618354, 28492532
SCV004198861	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 28, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004841648	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Sep 17, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20618354, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000639349

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 29, 2023)

germline

clinical testing

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

SCV004198861

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 28, 2023)

unknown

clinical testing

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

SCV004841648

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Sep 17, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Citations

PubMed

Analysis of MUTYH genotypes and colorectal phenotypes in patients With MUTYH-associated polyposis.

Nielsen M, Joerink-van de Beld MC, Jones N, Vogt S, Tops CM, Vasen HF, Sampson JR, Aretz S, Hes FJ.

Gastroenterology. 2009 Feb;136(2):471-6. doi: 10.1053/j.gastro.2008.10.056. Epub 2008 Oct 30.

PubMed [citation]

PMID:: 19032956

Expanded extracolonic tumor spectrum in MUTYH-associated polyposis.

Vogt S, Jones N, Christian D, Engel C, Nielsen M, Kaufmann A, Steinke V, Vasen HF, Propping P, Sampson JR, Hes FJ, Aretz S.

Gastroenterology. 2009 Dec;137(6):1976-85.e1-10. doi: 10.1053/j.gastro.2009.08.052. Epub 2009 Sep 2.

PubMed [citation]

PMID:: 19732775

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000639349.9

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

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 215 of the MUTYH protein (p.Val215Met). This variant is present in population databases (rs776487884, gnomAD 0.03%). This missense change has been observed in individual(s) with MUTYH-associated polyposis syndrome (PMID: 19032956, 19732775, 20618354; Invitae; externalcommunication). 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: 184952). 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 disruptive. For these reasons, this variant has been classified as 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 Baylor Genetics, SCV004198861.2

#	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, SCV004841648.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces valine with methionine at codon 215 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer with more than 100 colorectal polyps and a pathogenic MUTYH co-variant c.884C>T (p.Pro295Leu)(PMID: 20618354). This variant has also been identified in the compound heterozygous state in an individual affected with multiple adenomatous polyps and in the homozygous state in an individual affected with colon cancer and colorectal polyps (communication with an external laboratory; ClinVar SCV000214928.5). This variant has been identified in 12/251426 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely 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		4	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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