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NM_001048174.2(MUTYH):c.1321G>A (p.Val441Ile) AND Hereditary cancer-predisposing syndrome

Germline classification:
Uncertain significance (3 submissions)
Last evaluated:
Oct 2, 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:
RCV000166365.13

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1321G>A (p.Val441Ile)]

NM_001048174.2(MUTYH):c.1321G>A (p.Val441Ile)

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.1321G>A (p.Val441Ile)
HGVS:
  • NC_000001.11:g.45331253C>T
  • NG_008189.1:g.14218G>A
  • NM_001048171.2:c.1321G>A
  • NM_001048172.2:c.1324G>A
  • NM_001048173.2:c.1321G>A
  • NM_001048174.2:c.1321G>AMANE SELECT
  • NM_001128425.2:c.1405G>A
  • NM_001293190.2:c.1366G>A
  • NM_001293191.2:c.1354G>A
  • NM_001293192.2:c.1045G>A
  • NM_001293195.2:c.1321G>A
  • NM_001293196.2:c.1045G>A
  • NM_001350650.2:c.976G>A
  • NM_001350651.2:c.976G>A
  • NM_012222.3:c.1396G>A
  • NP_001041636.1:p.Val455Ile
  • NP_001041636.2:p.Val441Ile
  • NP_001041637.1:p.Val442Ile
  • NP_001041638.1:p.Val441Ile
  • NP_001041639.1:p.Val441Ile
  • NP_001121897.1:p.Val469Ile
  • NP_001121897.1:p.Val469Ile
  • NP_001280119.1:p.Val456Ile
  • NP_001280120.1:p.Val452Ile
  • NP_001280121.1:p.Val349Ile
  • NP_001280124.1:p.Val441Ile
  • NP_001280125.1:p.Val349Ile
  • NP_001337579.1:p.Val326Ile
  • NP_001337580.1:p.Val326Ile
  • NP_036354.1:p.Val466Ile
  • LRG_220t1:c.1405G>A
  • LRG_220:g.14218G>A
  • LRG_220p1:p.Val469Ile
  • NC_000001.10:g.45796925C>T
  • NM_001048171.1:c.1363G>A
  • NM_001128425.1:c.1405G>A
  • NR_146882.2:n.1549G>A
  • NR_146883.2:n.1398G>A
  • p.V469I
Protein change:
V326I
Links:
dbSNP: rs779701238
NCBI 1000 Genomes Browser:
rs779701238
Molecular consequence:
  • NM_001048171.2:c.1321G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048172.2:c.1324G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048173.2:c.1321G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048174.2:c.1321G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001128425.2:c.1405G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293190.2:c.1366G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293191.2:c.1354G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293192.2:c.1045G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293195.2:c.1321G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293196.2:c.1045G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350650.2:c.976G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350651.2:c.976G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_012222.3:c.1396G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_146882.2:n.1549G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_146883.2:n.1398G>A - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000217154Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Uncertain significance
(Oct 2, 2023)
germlineclinical testing

Citation Link,

SCV000685572Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Aug 28, 2023)
germlineclinical testing

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

SCV002532232Sema4, Sema4
criteria provided, single submitter

(Sema4 Curation Guidelines)
Uncertain significance
(Jun 18, 2021)
germlinecuration

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]
PMID:
33471991
PMCID:
PMC7611105

Details of each submission

From Ambry Genetics, SCV000217154.7

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

Description

The p.V469I variant (also known as c.1405G>A), located in coding exon 14 of the MUTYH gene, results from a G to A substitution at nucleotide position 1405. The valine at codon 469 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

From Color Diagnostics, LLC DBA Color Health, SCV000685572.5

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

Description

This missense variant replaces valine with isoleucine at codon 469 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 4/251492 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.

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

From Sema4, Sema4, SCV002532232.1

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

Last Updated: Oct 13, 2024