NM_001048174.2(MUTYH):c.616G>A (p.Val206Met) AND not provided

Germline classification:: Conflicting classifications of pathogenicity (4 submissions)
Last evaluated:: Oct 21, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000586141.21

Allele description [Variation Report for NM_001048174.2(MUTYH):c.616G>A (p.Val206Met)]

NM_001048174.2(MUTYH):c.616G>A (p.Val206Met)

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.616G>A (p.Val206Met)

Other names:

p.V234M:GTG>ATG

HGVS:

NC_000001.11:g.45332479C>T
NG_008189.1:g.12992G>A
NM_001048171.2:c.616G>A
NM_001048172.2:c.619G>A
NM_001048173.2:c.616G>A
NM_001048174.2:c.616G>AMANE SELECT
NM_001128425.2:c.700G>A
NM_001293190.2:c.661G>A
NM_001293191.2:c.649G>A
NM_001293192.2:c.340G>A
NM_001293195.2:c.616G>A
NM_001293196.2:c.340G>A
NM_001350650.2:c.271G>A
NM_001350651.2:c.271G>A
NM_012222.3:c.691G>A
NP_001041636.1:p.Val220Met
NP_001041636.2:p.Val206Met
NP_001041637.1:p.Val207Met
NP_001041638.1:p.Val206Met
NP_001041639.1:p.Val206Met
NP_001121897.1:p.Val234Met
NP_001121897.1:p.Val234Met
NP_001280119.1:p.Val221Met
NP_001280120.1:p.Val217Met
NP_001280121.1:p.Val114Met
NP_001280124.1:p.Val206Met
NP_001280125.1:p.Val114Met
NP_001337579.1:p.Val91Met
NP_001337580.1:p.Val91Met
NP_036354.1:p.Val231Met
LRG_220t1:c.700G>A
LRG_220:g.12992G>A
LRG_220p1:p.Val234Met
NC_000001.10:g.45798151C>T
NM_001048171.1:c.658G>A
NM_001128425.1:c.700G>A
NR_146882.2:n.844G>A
NR_146883.2:n.693G>A
p.V234M

Protein change:

V114M

Links:

dbSNP: rs200165598

NCBI 1000 Genomes Browser:

rs200165598

Molecular consequence:

NM_001048171.2:c.616G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.619G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.616G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.616G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.700G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.661G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.649G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.340G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.616G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.340G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.271G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.271G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.691G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.844G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.693G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000211403	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Aug 12, 2024)	germline	clinical testing	Citation Link,
SCV000806366	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 25, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000889534	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	likely pathogenic (Oct 21, 2024)	unknown	clinical testing	PubMed (14) [See all records that cite these PMIDs] 30374176, 36744932, 14991577, 25820570, 26694661, 16774938, 25980754, 31422818, 34326862, 33850299, 33436027, 28944238, 33471991, 26467025
SCV001159672	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain significance (Sep 28, 2023)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

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

Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance.

Tsai GJ, Rañola JMO, Smith C, Garrett LT, Bergquist T, Casadei S, Bowen DJ, Shirts BH.

Genet Med. 2019 Jun;21(6):1435-1442. doi: 10.1038/s41436-018-0335-7. Epub 2018 Oct 30.

PubMed [citation]

PMID:: 30374176

See all PubMed Citations (15)

Details of each submission

From GeneDx, SCV000211403.17

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

Description

Observed as heterozygous in individuals with colon cancer as well as in healthy controls (PMID: 16774938, 14991577); Published functional studies demonstrate partially defective base excision repair activity, but DNA glycosylase activity and mutation suppression ability similar to wild-type (PMID: 25820570, 26694661); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as c.658G>A p.(V220M); This variant is associated with the following publications: (PMID: 19725997, 20725929, 14991577, 16774938, 25820570, 15465463, 25980754, 26694661, 28944238, 33436027, 29360161, 26580448, 26377631, 15326180, 9846876, 17581577, 17161978, 35034041, 31422818, 23108399, 11801590, 37357966, 33471991, 38196581, 33850299, 34326862, 30374176, 36744932)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From PreventionGenetics, part of Exact Sciences, SCV000806366.1

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

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000889534.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

The MUTYH c.700G>A (p.Val234Met) variant has been reported in the published literature in individuals affected with Lynch syndrome-associated cancers and/or polyps (PMID: 16774938 (2006), 14991577 (2004), 25980754 (2015), 28944238 (2017), 31422818 (2019), 33436027 (2021)), breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)), endometrial cancer (PMID: 36744932 (2023)) and hematological malignancies (PMID: 33850299 (2021)). This variant has also been observed in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). This variant was determined to segregate with disease in five siblings, each of whom were also positive for a known MUTYH pathogenic variant (c.536A>G, p.Tyr179Cys) and a documented history of colon cancer and/or over 20 colonic polyps (PMID: 30374176 (2019)). Functional studies examining the effect of this variant on MUTYH protein function have yielded conflicting results (PMID: 25820570 (2015), 26694661 (2016)). The frequency of this variant in the general population, 0.00018 (23/128662 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001159672.2

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

Description

The MUTYH c.700G>A; p.Val234Met variant (rs200165598), also known as Val220Met for traditional nomenclature, is reported in the literature in individuals with colorectal cancer but a second MUTYH variant was not identified (Fleischmann 2004, Peterlongo 2006, Yurgelun 2015). Our laboratory has identified this variant previously in an individual with a personal and family history of colon cancer, who also carried a pathogenic MUTYH frameshift variant. One functional study shows that the p.Val234Met variant protein has partially defective function (Komine 2015), while another study shows the variant protein retains normal repair activity (Shinmura 2016). This variant is reported in ClinVar (Variation ID: 135989). It is found in the general European (non-Finnish) population with an allele frequency of 0.02% (23/128662 alleles) in the Genome Aggregation Database. Due to limited information, the significance of this variant is uncertain at this time. REFERENCES Fleischmann C et al. Comprehensive analysis of the contribution of germline MYH variation to early-onset colorectal cancer. Int J Cancer. 2004 Apr 20;109(4):554-8. Komine K et al. Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain. Hum Mutat. 2015 Jul;36(7):704-11. Peterlongo P et al. Increased frequency of disease-causing MYH mutations in colon cancer families. Carcinogenesis. 2006 Nov;27(11):2243-9. Shinmura K et al. Functional Evaluation of Nine Missense-Type Variants of the Human DNA Glycosylase Enzyme MUTYH in the Japanese Population. Hum Mutat. 2016 Apr;37(4):350-3. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20.

#	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: Jan 19, 2025

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