NM_001048174.2(MUTYH):c.22G>T (p.Val8Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 26, 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:: RCV000566823.7

Allele description [Variation Report for NM_001048174.2(MUTYH):c.22G>T (p.Val8Leu)]

NM_001048174.2(MUTYH):c.22G>T (p.Val8Leu)

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.22G>T (p.Val8Leu)

HGVS:

NC_000001.11:g.45334484C>A
NG_008189.1:g.10987G>T
NM_001048171.2:c.22G>T
NM_001048172.2:c.22G>T
NM_001048173.2:c.22G>T
NM_001048174.2:c.22G>TMANE SELECT
NM_001128425.2:c.64G>T
NM_001293190.2:c.64G>T
NM_001293191.2:c.22G>T
NM_001293192.2:c.-191G>T
NM_001293195.2:c.22G>T
NM_001293196.2:c.-191G>T
NM_001350650.2:c.-250G>T
NM_001350651.2:c.-186G>T
NM_012222.3:c.64G>T
NP_001041636.2:p.Val8Leu
NP_001041637.1:p.Val8Leu
NP_001041638.1:p.Val8Leu
NP_001041639.1:p.Val8Leu
NP_001121897.1:p.Val22Leu
NP_001121897.1:p.Val22Leu
NP_001280119.1:p.Val22Leu
NP_001280120.1:p.Val8Leu
NP_001280124.1:p.Val8Leu
NP_036354.1:p.Val22Leu
LRG_220t1:c.64G>T
LRG_220:g.10987G>T
LRG_220p1:p.Val22Leu
NC_000001.10:g.45800156C>A
NM_001128425.1:c.64G>T
NR_146882.2:n.250G>T
NR_146883.2:n.173G>T

Protein change:

V22L

Links:

dbSNP: rs3219484

NCBI 1000 Genomes Browser:

rs3219484

Molecular consequence:

NM_001293192.2:c.-191G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001293196.2:c.-191G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350650.2:c.-250G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350651.2:c.-186G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001048171.2:c.22G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.22G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.22G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.22G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.64G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.64G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.22G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.22G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.64G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.250G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.173G>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
SCV000670125	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 16, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20149637, 23605219, 24039736, 28608266, 29458332, 30098577, 32072083 Citation Link,
SCV000913066	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 26, 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

SCV000670125

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Apr 16, 2021)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV000913066

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 26, 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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Common variants in human CRC genes as low-risk alleles.

Picelli S, Zajac P, Zhou XL, Edler D, Lenander C, Dalén J, Hjern F, Lundqvist N, Lindforss U, Påhlman L, Smedh K, Törnqvist A, Holm J, Janson M, Andersson M, Ekelund S, Olsson L, Lundeberg J, Lindblom A.

Eur J Cancer. 2010 Apr;46(6):1041-8. doi: 10.1016/j.ejca.2010.01.013. Epub 2010 Feb 9.

PubMed [citation]

PMID:: 20149637

MUTYH-associated colorectal cancer and adenomatous polyposis.

Yamaguchi S, Ogata H, Katsumata D, Nakajima M, Fujii T, Tsutsumi S, Asao T, Sasaki K, Kuwano H, Kato H.

Surg Today. 2014 Apr;44(4):593-600. doi: 10.1007/s00595-013-0592-7. Epub 2013 Apr 19. Review.

PubMed [citation]

PMID:: 23605219

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000670125.5

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

Description

The p.V22L variant (also known as c.64G>T), located in coding exon 2 of the MUTYH gene, results from a G to T substitution at nucleotide position 64. The valine at codon 22 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not well 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.

#	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, SCV000913066.3

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

Description

This missense variant replaces valine with leucine at codon 22 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 not been identified 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.

#	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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