NM_001048174.2(MUTYH):c.397G>C (p.Asp133His) AND Familial adenomatous polyposis 2

Germline classification:: Uncertain significance (6 submissions)
Last evaluated:: Jul 29, 2024
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:: RCV000204817.20

Allele description [Variation Report for NM_001048174.2(MUTYH):c.397G>C (p.Asp133His)]

NM_001048174.2(MUTYH):c.397G>C (p.Asp133His)

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.397G>C (p.Asp133His)

HGVS:

NC_000001.11:g.45332941C>G
NG_008189.1:g.12530G>C
NM_001048171.2:c.397G>C
NM_001048172.2:c.400G>C
NM_001048173.2:c.397G>C
NM_001048174.2:c.397G>CMANE SELECT
NM_001128425.2:c.481G>C
NM_001293190.2:c.442G>C
NM_001293191.2:c.430G>C
NM_001293192.2:c.121G>C
NM_001293195.2:c.397G>C
NM_001293196.2:c.121G>C
NM_001350650.2:c.52G>C
NM_001350651.2:c.52G>C
NM_012222.3:c.472G>C
NP_001041636.1:p.Asp147His
NP_001041636.2:p.Asp133His
NP_001041637.1:p.Asp134His
NP_001041638.1:p.Asp133His
NP_001041639.1:p.Asp133His
NP_001121897.1:p.Asp161His
NP_001121897.1:p.Asp161His
NP_001280119.1:p.Asp148His
NP_001280120.1:p.Asp144His
NP_001280121.1:p.Asp41His
NP_001280124.1:p.Asp133His
NP_001280125.1:p.Asp41His
NP_001337579.1:p.Asp18His
NP_001337580.1:p.Asp18His
NP_036354.1:p.Asp158His
LRG_220t1:c.481G>C
LRG_220:g.12530G>C
LRG_220p1:p.Asp161His
NC_000001.10:g.45798613C>G
NM_001048171.1:c.439G>C
NM_001128425.1:c.481G>C
NR_146882.2:n.625G>C
NR_146883.2:n.474G>C
p.D161H

Protein change:

D133H

Links:

dbSNP: rs564930066

NCBI 1000 Genomes Browser:

rs564930066

Molecular consequence:

NM_001048171.2:c.397G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.400G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.397G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.397G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.481G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.442G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.430G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.121G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.397G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.121G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.52G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.52G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.472G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.625G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.474G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Familial adenomatous polyposis 2
Synonyms:: COLORECTAL ADENOMATOUS POLYPOSIS, AUTOSOMAL RECESSIVE; ADENOMAS, MULTIPLE COLORECTAL, AUTOSOMAL RECESSIVE; MYH-associated polyposis; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012041; MedGen: C3272841; Orphanet: 220460; OMIM: 608456

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000260661	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 9, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21424714, 25980754, 27443514, 30093976, 35264596, 28492532
SCV000487330	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Uncertain significance (Dec 30, 2015)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25980754, 21777424 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000837777	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV002512304	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 26, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004198863	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 17, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005429858	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jul 29, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 21424714, 25938944, 25980754, 27443514, 29684080, 30093976, 33471991, 35264596, 38060977, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	22	not provided	not provided	143475	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

High resolution melting analysis for a rapid identification of heterozygous and homozygous sequence changes in the MUTYH gene.

Tricarico R, Crucianelli F, Alvau A, Orlando C, Sestini R, Tonelli F, Valanzano R, Genuardi M.

BMC Cancer. 2011 Jul 21;11:305. doi: 10.1186/1471-2407-11-305.

PubMed [citation]

PMID:: 21777424
PMCID:: PMC3156810

See all PubMed Citations (12)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000260661.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 161 of the MUTYH protein (p.Asp161His). This variant is present in population databases (rs564930066, gnomAD 0.05%). This missense change has been observed in individual(s) with breast cancer, clinical features of MUTYH-associated polyposis (MAP), and/or endometrial cancer (PMID: 21424714, 25980754, 27443514, 30093976, 35264596; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 140814). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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

From Counsyl, SCV000487330.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	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 Mendelics, SCV000837777.2

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

#	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 Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV002512304.1

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

Description

ACMG classification criteria: PS4 supporting, PM2 moderate

#	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 Baylor Genetics, SCV004198863.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV005429858.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	22	not provided	not provided	clinical testing	PubMed (10)

Description

This missense variant replaces aspartic acid with histidine at codon 161 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least three biallelic individuals affected with colorectal cancer and/or MUTYH-associated polyposis (PMID: 21424714, 25938944; ClinVar Accession: SCV000172897.8). This variant has also been detected in two individuals who were tested for Lynch syndrome (PMID: 25980754, 38060977), two individuals affected with endometrial cancer (PMID: 27443514), an individual affected with prostate cancer (PMID: 30093976), an individual affected with either Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (PMID: 29684080), and several individuals affected with breast cancer (PMID: 35264596). In an international breast cancer case-control meta-analysis, this variant was detected in 5/60466 cases and 14/53461 unaffected controls (OR=0.316, 95%CI 0.114 to 0.877, p-value=0.022; PMID: 33471991). This variant has been identified in 29/281806 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	143475	not provided	not provided		22	not provided	not provided	not provided

Last Updated: Jan 19, 2025

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