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NM_001048174.2(MUTYH):c.566G>A (p.Arg189His) AND Carcinoma of colon

Germline classification:
Uncertain significance (1 submission)
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV000482890.5

Allele description [Variation Report for NM_001048174.2(MUTYH):c.566G>A (p.Arg189His)]

NM_001048174.2(MUTYH):c.566G>A (p.Arg189His)

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.566G>A (p.Arg189His)
HGVS:
  • NC_000001.11:g.45332614C>T
  • NG_008189.1:g.12857G>A
  • NM_001048171.2:c.566G>A
  • NM_001048172.2:c.569G>A
  • NM_001048173.2:c.566G>A
  • NM_001048174.2:c.566G>AMANE SELECT
  • NM_001128425.2:c.650G>A
  • NM_001293190.2:c.611G>A
  • NM_001293191.2:c.599G>A
  • NM_001293192.2:c.290G>A
  • NM_001293195.2:c.566G>A
  • NM_001293196.2:c.290G>A
  • NM_001350650.2:c.221G>A
  • NM_001350651.2:c.221G>A
  • NM_012222.3:c.641G>A
  • NP_001041636.1:p.Arg203His
  • NP_001041636.2:p.Arg189His
  • NP_001041637.1:p.Arg190His
  • NP_001041638.1:p.Arg189His
  • NP_001041639.1:p.Arg189His
  • NP_001121897.1:p.Arg217His
  • NP_001121897.1:p.Arg217His
  • NP_001280119.1:p.Arg204His
  • NP_001280120.1:p.Arg200His
  • NP_001280121.1:p.Arg97His
  • NP_001280124.1:p.Arg189His
  • NP_001280125.1:p.Arg97His
  • NP_001337579.1:p.Arg74His
  • NP_001337580.1:p.Arg74His
  • NP_036354.1:p.Arg214His
  • LRG_220t1:c.650G>A
  • LRG_220:g.12857G>A
  • LRG_220p1:p.Arg217His
  • NC_000001.10:g.45798286C>T
  • NM_001048171.1:c.608G>A
  • NM_001128425.1:c.650G>A
  • NR_146882.2:n.794G>A
  • NR_146883.2:n.643G>A
  • p.R217H
Protein change:
R189H
Links:
dbSNP: rs147754007
NCBI 1000 Genomes Browser:
rs147754007
Molecular consequence:
  • NM_001048171.2:c.566G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048172.2:c.569G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048173.2:c.566G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048174.2:c.566G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001128425.2:c.650G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293190.2:c.611G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293191.2:c.599G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293192.2:c.290G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293195.2:c.566G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293196.2:c.290G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350650.2:c.221G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350651.2:c.221G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_012222.3:c.641G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_146882.2:n.794G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_146883.2:n.643G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Carcinoma of colon (CRC)
Synonyms:
Colonic carcinoma; Colon carcinoma
Identifiers:
MONDO: MONDO:0002032; MedGen: C0699790

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000592690Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Uncertain significanceunknownclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592690.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The MUTYH p.Arg217His variant was identified in APC-negative patients with more than 5 colorectal adenomas; the frequency of the variant in this cohort, zygosity and disease severity were not provided from this cohort (Olschwang 2007). It was also identified in a large Austrian kindred with Familial colorectal cancer type X (FCCTX), being studied for novel candidate gene mutations; but was excluded as the cause of neoplasms in this family due to non-segregation amongst family members (Schulz 2014). The variant was also identified in dbSNP (ID: rs147754007) as “With Uncertain significance allele”, Clinvitae database (classification uncertain significance), ClinVar database (classification uncertain significance by Ambry Genetics), UMD (2x with a ”unclassified variant” classification), NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles (frequency: 0.0001) and in 1 of 4406 African American alleles (frequency: 0.0002), and the Exome Aggregation Consortium database (March 14, 2016) in 5 of 121252 chromosomes (freq. 0.00004) in the following populations: Latino in 1 of 11572 chromosomes (freq. 00009), South Asian in 1 of 16512 chromosomes (freq. 0.00006), European (Non-Finnish) in 3 of 66638 chromosomes (freq. 0.00005), but was not seen in African, East Asian, Finnish, and Other populations, increasing the likelihood this could be a low frequency benign variant. The p.Arg217 residue is conserved across mammals and lower organisms, and three out of four computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the His variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024