NM_001048174.2(MUTYH):c.1463C>T (p.Pro488Leu) AND Familial adenomatous polyposis 2

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 26, 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:: RCV000457983.14

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1463C>T (p.Pro488Leu)]

NM_001048174.2(MUTYH):c.1463C>T (p.Pro488Leu)

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.1463C>T (p.Pro488Leu)

HGVS:

NC_000001.11:g.45329409G>A
NG_008189.1:g.16062C>T
NM_001048171.2:c.1463C>T
NM_001048172.2:c.1466C>T
NM_001048173.2:c.1463C>T
NM_001048174.2:c.1463C>TMANE SELECT
NM_001128425.2:c.1547C>T
NM_001293190.2:c.1508C>T
NM_001293191.2:c.1496C>T
NM_001293192.2:c.1187C>T
NM_001293195.2:c.1463C>T
NM_001293196.2:c.1187C>T
NM_001350650.2:c.1118C>T
NM_001350651.2:c.1118C>T
NM_012222.3:c.1538C>T
NP_001041636.2:p.Pro488Leu
NP_001041637.1:p.Pro489Leu
NP_001041638.1:p.Pro488Leu
NP_001041639.1:p.Pro488Leu
NP_001121897.1:p.Pro516Leu
NP_001121897.1:p.Pro516Leu
NP_001280119.1:p.Pro503Leu
NP_001280120.1:p.Pro499Leu
NP_001280121.1:p.Pro396Leu
NP_001280124.1:p.Pro488Leu
NP_001280125.1:p.Pro396Leu
NP_001337579.1:p.Pro373Leu
NP_001337580.1:p.Pro373Leu
NP_036354.1:p.Pro513Leu
LRG_220t1:c.1547C>T
LRG_220:g.16062C>T
LRG_220p1:p.Pro516Leu
NC_000001.10:g.45795081G>A
NM_001128425.1:c.1547C>T
NR_146882.2:n.1871C>T
NR_146883.2:n.1720C>T
p.P516L

Protein change:

P373L

Links:

dbSNP: rs587778542

NCBI 1000 Genomes Browser:

rs587778542

Molecular consequence:

NM_001048171.2:c.1463C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.1466C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.1463C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.1463C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.1547C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.1508C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.1496C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.1187C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.1463C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.1187C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.1118C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.1118C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.1538C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.1871C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.1720C>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
SCV000545757	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 26, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20618354, 25820570, 26377631, 28492532
SCV000837742	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV004830916	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Aug 15, 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

SCV000545757

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 26, 2024)

germline

clinical testing

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

SCV000837742

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Uncertain significance
(Jul 2, 2018)

unknown

clinical testing

Citation Link,

SCV004830916

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Benign
(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	germline	unknown	3	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

MUTYH-associated polyposis - variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations.

Morak M, Laner A, Bacher U, Keiling C, Holinski-Feder E.

Clin Genet. 2010 Oct;78(4):353-63. doi: 10.1111/j.1399-0004.2010.01478.x.

PubMed [citation]

PMID:: 20618354

Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain.

Komine K, Shimodaira H, Takao M, Soeda H, Zhang X, Takahashi M, Ishioka C.

Hum Mutat. 2015 Jul;36(7):704-11. doi: 10.1002/humu.22794.

PubMed [citation]

PMID:: 25820570
PMCID:: PMC4682456

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000545757.10

#	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 proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 516 of the MUTYH protein (p.Pro516Leu). This variant is present in population databases (rs587778542, gnomAD 0.004%). This missense change has been observed in individual(s) with attenuated familial adenomatous polyposis (PMID: 20618354). This variant is also known as p.P502L. ClinVar contains an entry for this variant (Variation ID: 134867). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect MUTYH function (PMID: 25820570, 26377631). 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 Mendelics, SCV000837742.2

#	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 All of Us Research Program, National Institutes of Health, SCV004830916.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	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		3	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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