NM_001128425.2(MUTYH):c.38C>T (p.Ala13Val) AND Familial adenomatous polyposis 2

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 19, 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:: RCV000123150.16

Allele description [Variation Report for NM_001128425.2(MUTYH):c.38C>T (p.Ala13Val)]

NM_001128425.2(MUTYH):c.38C>T (p.Ala13Val)

Gene:

MUTYH:mutY DNA glycosylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p34.1

Genomic location:

Preferred name:

NM_001128425.2(MUTYH):c.38C>T (p.Ala13Val)

HGVS:

NC_000001.11:g.45334510G>A
NG_008189.1:g.10961C>T
NM_001048171.2:c.-5C>T
NM_001048172.2:c.-5C>T
NM_001048173.2:c.-5C>T
NM_001048174.2:c.-5C>TMANE SELECT
NM_001128425.2:c.38C>T
NM_001293190.2:c.38C>T
NM_001293191.2:c.-5C>T
NM_001293192.2:c.-217C>T
NM_001293195.2:c.-5C>T
NM_001293196.2:c.-217C>T
NM_001350650.2:c.-276C>T
NM_001350651.2:c.-212C>T
NM_012222.3:c.38C>T
NP_001041636.1:p.Ala13Val
NP_001121897.1:p.Ala13Val
NP_001121897.1:p.Ala13Val
NP_001280119.1:p.Ala13Val
NP_036354.1:p.Ala13Val
LRG_220t1:c.38C>T
LRG_220:g.10961C>T
LRG_220p1:p.Ala13Val
NC_000001.10:g.45800182G>A
NM_001048171.1:c.38C>T
NM_001128425.1:c.38C>T
NR_146882.2:n.224C>T
NR_146883.2:n.147C>T
p.A13V

Protein change:

A13V

Links:

dbSNP: rs587780747

NCBI 1000 Genomes Browser:

rs587780747

Molecular consequence:

NM_001048171.2:c.-5C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001048172.2:c.-5C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001048173.2:c.-5C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001048174.2:c.-5C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001293191.2:c.-5C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001293192.2:c.-217C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001293195.2:c.-5C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001293196.2:c.-217C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350650.2:c.-276C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350651.2:c.-212C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001128425.2:c.38C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.38C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.38C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.224C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.147C>T - 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
SCV000166453	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 19, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34326862, 28492532
SCV000487325	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Uncertain significance (Dec 22, 2015)	unknown	clinical testing	mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV004835782	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 1, 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

SCV000166453

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 19, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000487325

Counsyl

criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))

Uncertain significance
(Dec 22, 2015)

unknown

clinical testing

mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf,

Citation Link,

SCV004835782

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 1, 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	4	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach.

Bhai P, Levy MA, Rooney K, Carere DA, Reilly J, Kerkhof J, Volodarsky M, Stuart A, Kadour M, Panabaker K, Schenkel LC, Lin H, Ainsworth P, Sadikovic B.

Front Genet. 2021;12:698595. doi: 10.3389/fgene.2021.698595.

PubMed [citation]

PMID:: 34326862
PMCID:: PMC8314385

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

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000166453.12

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 13 of the MUTYH protein (p.Ala13Val). This variant is present in population databases (rs587780747, gnomAD 0.003%). This missense change has been observed in individual(s) with MUTYH-related conditions (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 135987). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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, SCV000487325.2

#	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 All of Us Research Program, National Institutes of Health, SCV004835782.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (1)

Description

This missense variant replaces alanine with valine at codon 13 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 hereditary cancer in the literature. This variant has been identified in 3/251466 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	108544	not provided	not provided		4	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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