NM_001048174.2(MUTYH):c.1222C>G (p.Leu408Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Apr 9, 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:: RCV000130506.11

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1222C>G (p.Leu408Val)]

NM_001048174.2(MUTYH):c.1222C>G (p.Leu408Val)

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.1222C>G (p.Leu408Val)

HGVS:

NC_000001.11:g.45331437G>C
NG_008189.1:g.14034C>G
NM_001048171.2:c.1222C>G
NM_001048172.2:c.1225C>G
NM_001048173.2:c.1222C>G
NM_001048174.2:c.1222C>GMANE SELECT
NM_001128425.2:c.1306C>G
NM_001293190.2:c.1267C>G
NM_001293191.2:c.1255C>G
NM_001293192.2:c.946C>G
NM_001293195.2:c.1222C>G
NM_001293196.2:c.946C>G
NM_001350650.2:c.877C>G
NM_001350651.2:c.877C>G
NM_012222.3:c.1297C>G
NP_001041636.1:p.Leu422Val
NP_001041636.2:p.Leu408Val
NP_001041637.1:p.Leu409Val
NP_001041638.1:p.Leu408Val
NP_001041639.1:p.Leu408Val
NP_001121897.1:p.Leu436Val
NP_001121897.1:p.Leu436Val
NP_001280119.1:p.Leu423Val
NP_001280120.1:p.Leu419Val
NP_001280121.1:p.Leu316Val
NP_001280124.1:p.Leu408Val
NP_001280125.1:p.Leu316Val
NP_001337579.1:p.Leu293Val
NP_001337580.1:p.Leu293Val
NP_036354.1:p.Leu433Val
LRG_220t1:c.1306C>G
LRG_220:g.14034C>G
LRG_220p1:p.Leu436Val
NC_000001.10:g.45797109G>C
NM_001048171.1:c.1264C>G
NM_001128425.1:c.1306C>G
NR_146882.2:n.1450C>G
NR_146883.2:n.1299C>G
p.L436V

Protein change:

L293V

Links:

dbSNP: rs587782043

NCBI 1000 Genomes Browser:

rs587782043

Molecular consequence:

NM_001048171.2:c.1222C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.1225C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.1222C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.1222C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.1306C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.1267C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.1255C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.946C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.1222C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.946C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.877C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.877C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.1297C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.1450C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.1299C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Hereditary neoplastic syndrome; 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
SCV000185375	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 19, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000905852	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 19, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005045364	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 9, 2024)	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

SCV000185375

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Mar 19, 2024)

germline

clinical testing

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

Citation Link,

SCV000905852

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 19, 2020)

germline

clinical testing

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

SCV005045364

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 9, 2024)

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

Type and frequency of MUTYH variants in Italian patients with suspected MAP: a retrospective multicenter study.

Ricci MT, Miccoli S, Turchetti D, Bondavalli D, Viel A, Quaia M, Giacomini E, Gismondi V, Sanchez-Mete L, Stigliano V, Martayan A, Mazzei F, Bignami M, Bonelli L, Varesco L.

J Hum Genet. 2017 Feb;62(2):309-315. doi: 10.1038/jhg.2016.132. Epub 2016 Nov 10.

PubMed [citation]

PMID:: 27829682

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

Details of each submission

From Ambry Genetics, SCV000185375.9

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

Description

The p.L436V variant (also known as c.1306C>G), located in coding exon 13 of the MUTYH gene, results from a C to G substitution at nucleotide position 1306. The leucine at codon 436 is replaced by valine, an amino acid with highly similar properties. This variant has been reported in 1/299 Italian individuals with suspected MUTYH-associated polyposis (MAP) (Ricci MT et al. J. Hum. Genet., 2017 Feb;62:309-315). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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, SCV000905852.3

#	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 leucine with valine at codon 436 of the MUTYH protein. This variant is also known as c.1264C>G (p.Leu422Val) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer and/or colon polyp (PMID: 27829682). This variant has been identified in 2/251378 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C., SCV005045364.1

#	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

Last Updated: Jun 29, 2025

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