NM_001048174.2(MUTYH):c.386C>T (p.Pro129Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jun 14, 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:: RCV000165108.15

Allele description [Variation Report for NM_001048174.2(MUTYH):c.386C>T (p.Pro129Leu)]

NM_001048174.2(MUTYH):c.386C>T (p.Pro129Leu)

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.386C>T (p.Pro129Leu)

HGVS:

NC_000001.11:g.45332952G>A
NG_008189.1:g.12519C>T
NM_001048171.2:c.386C>T
NM_001048172.2:c.389C>T
NM_001048173.2:c.386C>T
NM_001048174.2:c.386C>TMANE SELECT
NM_001128425.2:c.470C>T
NM_001293190.2:c.431C>T
NM_001293191.2:c.419C>T
NM_001293192.2:c.110C>T
NM_001293195.2:c.386C>T
NM_001293196.2:c.110C>T
NM_001350650.2:c.41C>T
NM_001350651.2:c.41C>T
NM_012222.3:c.461C>T
NP_001041636.2:p.Pro129Leu
NP_001041637.1:p.Pro130Leu
NP_001041638.1:p.Pro129Leu
NP_001041639.1:p.Pro129Leu
NP_001121897.1:p.Pro157Leu
NP_001121897.1:p.Pro157Leu
NP_001280119.1:p.Pro144Leu
NP_001280120.1:p.Pro140Leu
NP_001280121.1:p.Pro37Leu
NP_001280124.1:p.Pro129Leu
NP_001280125.1:p.Pro37Leu
NP_001337579.1:p.Pro14Leu
NP_001337580.1:p.Pro14Leu
NP_036354.1:p.Pro154Leu
LRG_220t1:c.470C>T
LRG_220:g.12519C>T
LRG_220p1:p.Pro157Leu
NC_000001.10:g.45798624G>A
NM_001128425.1:c.470C>T
NR_146882.2:n.614C>T
NR_146883.2:n.463C>T
p.P157L

Protein change:

P129L

Links:

dbSNP: rs777184451

NCBI 1000 Genomes Browser:

rs777184451

Molecular consequence:

NM_001048171.2:c.386C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.389C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.386C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.386C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.470C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.431C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.419C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.110C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.386C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.110C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.41C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.41C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.461C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.614C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.463C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000215818	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Mar 27, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16557584, 19032956, 19732775, 25820570, 27829682 Citation Link,
SCV000905865	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 14, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16557584, 19032956, 19394335, 19732775, 25820570, 27829682, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000215818

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Mar 27, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV000905865

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 14, 2023)

germline

clinical testing

PubMed (7)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype.

Aretz S, Uhlhaas S, Goergens H, Siberg K, Vogel M, Pagenstecher C, Mangold E, Caspari R, Propping P, Friedl W.

Int J Cancer. 2006 Aug 15;119(4):807-14.

PubMed [citation]

PMID:: 16557584

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

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000215818.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.P157L variant (also known as c.470C>T), located in coding exon 6 of the MUTYH gene, results from a C to T substitution at nucleotide position 470. The proline at codon 157 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in conjunction with a pathogenic MUTYH mutation in an individual with an attenuated polyposis phenotype; however, the phase (cis vs trans) of these two alterations was not determined (Aretz S et al. Int. J. Cancer 2006 Aug;119(4):807-14; Vogt S et al. Gastroenterology 2009 Dec;137(6):1976-85.e1-10). There is another report of this alteration being identified in an Italian individual with polyps at age 45 in conjunction with a different pathogenic MUTYH mutation (Ricci MT et al. J. Hum. Genet. 2017 Feb;62(2):309-315). This alteration has also been identified in our clinical laboratory in conjunction with pathogenic MUTYH mutations in individuals with adenomatous polyps, but the phase of these alterations was not determined (Ambry internal data). In a functional study, the ability of human MUTYH variant proteins to complement a Mut-deficient E. coli strain was measured and this variant demonstrated partially defective function; however, protein expression and subcellular localization were similar to wild type MUTYH (Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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 Color Diagnostics, LLC DBA Color Health, SCV000905865.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant replaces proline with leucine at codon 157 of the MUTYH protein. This variant is also known as c.428C>T (p.Pro143Leu) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes a partial loss of MUTYH protein function in vitro (PMID: 25820570). This variant has been reported in at least two biallelic individuals (PMID: 16557584, 19032956 19732775, 27829682) and a homozygous individual affected with multiple adenomatous polyposis and/or colorectal cancer (PMID: 19394335). This variant has been identified in 2/281716 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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