NM_001048171.1(MUTYH):c.1033C>A (p.Pro345Thr) AND Hereditary cancer-predisposing syndrome

Clinical significance:Uncertain significance (Last evaluated: Sep 3, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_001048171.1(MUTYH):c.1033C>A (p.Pro345Thr)]

NM_001048171.1(MUTYH):c.1033C>A (p.Pro345Thr)

MUTYH:mutY DNA glycosylase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_001048171.1(MUTYH):c.1033C>A (p.Pro345Thr)
  • NC_000001.11:g.45331772G>T
  • NG_008189.1:g.13699C>A
  • NM_001048171.1:c.1033C>A
  • NM_001048172.1:c.994C>A
  • NM_001048173.1:c.991C>A
  • NM_001048174.1:c.991C>A
  • NM_001128425.1:c.1075C>A
  • NM_001293190.1:c.1036C>A
  • NM_001293191.1:c.1024C>A
  • NM_001293192.1:c.715C>A
  • NM_001293195.1:c.991C>A
  • NM_001293196.1:c.715C>A
  • NM_001350650.1:c.646C>A
  • NM_001350651.1:c.646C>A
  • NM_012222.2:c.1066C>A
  • NP_001041636.1:p.Pro345Thr
  • NP_001041637.1:p.Pro332Thr
  • NP_001041638.1:p.Pro331Thr
  • NP_001041639.1:p.Pro331Thr
  • NP_001121897.1:p.Pro359Thr
  • NP_001280119.1:p.Pro346Thr
  • NP_001280120.1:p.Pro342Thr
  • NP_001280121.1:p.Pro239Thr
  • NP_001280124.1:p.Pro331Thr
  • NP_001280125.1:p.Pro239Thr
  • NP_001337579.1:p.Pro216Thr
  • NP_001337580.1:p.Pro216Thr
  • NP_036354.1:p.Pro356Thr
  • LRG_220t1:c.1075C>A
  • LRG_220:g.13699C>A
  • LRG_220p1:p.Pro359Thr
  • NC_000001.10:g.45797444G>T
  • NR_146882.1:n.1249C>A
  • NR_146883.1:n.1063C>A
  • p.P359T
Protein change:
dbSNP: rs587782773
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001048171.1:c.1033C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048172.1:c.994C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048173.1:c.991C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048174.1:c.991C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001128425.1:c.1075C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293190.1:c.1036C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293191.1:c.1024C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293192.1:c.715C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293195.1:c.991C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293196.1:c.715C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350650.1:c.646C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350651.1:c.646C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_012222.2:c.1066C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_146882.1:n.1249C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_146883.1:n.1063C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]


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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000187388Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Sep 3, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000690497Color Health, Inccriteria provided, single submitter
Uncertain significance
(Nov 7, 2019)
germlineclinical testing

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


This missense variant replaces proline with threonine at codon 359 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in 1 individual affected with colorectal cancer who has another MUTYH variant (PMID: 28944238). This variant has been identified in 4/280336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.


Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



MUTYH-associated polyposis--from defect in base excision repair to clinical genetic testing.

Cheadle JP, Sampson JR.

DNA Repair (Amst). 2007 Mar 1;6(3):274-9. Epub 2006 Dec 11. Review.

PubMed [citation]

Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes.

DeRycke MS, Gunawardena S, Balcom JR, Pickart AM, Waltman LA, French AJ, McDonnell S, Riska SM, Fogarty ZC, Larson MC, Middha S, Eckloff BW, Asmann YW, Ferber MJ, Haile RW, Gallinger S, Clendenning M, Rosty C, Win AK, Buchanan DD, Hopper JL, Newcomb PA, et al.

Mol Genet Genomic Med. 2017 Sep;5(5):553-569. doi: 10.1002/mgg3.317.

PubMed [citation]
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000187388.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)


The p.P359T variant (also known as c.1075C>A), located in coding exon 12 of the MUTYH gene, results from a C to A substitution at nucleotide position 1075. The proline at codon 359 is replaced by threonine, an amino acid with highly similar properties. This variant has been reported in the literature as an undefined rare variant that was identified in combination with another MUTYH mutation in a patient who had colorectal cancer diagnosed under the age of sixty with at least two affected family members; however, phase for the two variants (whether in cis or trans) was not determined (Cheadle JP and Sampson JR. DNA Repair (Amst.) 2007 Mar; 6(3):274-9). This alteration was also identified in an individual in conjunction with the p.Y179C MUTYH pathogenic variant; however, phase for the two variants was not determined. Furthermore, the individual in which these two MUTYH variants were identified met Amsterdam I criteria for Lynch syndrome, but had normal mismatch repair (MMR) function by tumor testing which demonstrated microsatellite stability and/or normal expression of the four MMR proteins (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). Of note, this alteration is also designated as c.1033C>A (p.P345T) in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV000690497.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2021

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