NM_001048174.2(MUTYH):c.1232T>C (p.Leu411Pro) AND Familial adenomatous polyposis 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 30, 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:: RCV000123144.9

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1232T>C (p.Leu411Pro)]

NM_001048174.2(MUTYH):c.1232T>C (p.Leu411Pro)

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.1232T>C (p.Leu411Pro)

HGVS:

NC_000001.11:g.45331427A>G
NG_008189.1:g.14044T>C
NM_001048171.2:c.1232T>C
NM_001048172.2:c.1235T>C
NM_001048173.2:c.1232T>C
NM_001048174.2:c.1232T>CMANE SELECT
NM_001128425.2:c.1316T>C
NM_001293190.2:c.1277T>C
NM_001293191.2:c.1265T>C
NM_001293192.2:c.956T>C
NM_001293195.2:c.1232T>C
NM_001293196.2:c.956T>C
NM_001350650.2:c.887T>C
NM_001350651.2:c.887T>C
NM_012222.3:c.1307T>C
NP_001041636.2:p.Leu411Pro
NP_001041637.1:p.Leu412Pro
NP_001041638.1:p.Leu411Pro
NP_001041639.1:p.Leu411Pro
NP_001121897.1:p.Leu439Pro
NP_001121897.1:p.Leu439Pro
NP_001280119.1:p.Leu426Pro
NP_001280120.1:p.Leu422Pro
NP_001280121.1:p.Leu319Pro
NP_001280124.1:p.Leu411Pro
NP_001280125.1:p.Leu319Pro
NP_001337579.1:p.Leu296Pro
NP_001337580.1:p.Leu296Pro
NP_036354.1:p.Leu436Pro
LRG_220t1:c.1316T>C
LRG_220:g.14044T>C
LRG_220p1:p.Leu439Pro
NC_000001.10:g.45797099A>G
NM_001128425.1:c.1316T>C
NR_146882.2:n.1460T>C
NR_146883.2:n.1309T>C

Protein change:

L296P

Links:

dbSNP: rs587780745

NCBI 1000 Genomes Browser:

rs587780745

Molecular consequence:

NM_001048171.2:c.1232T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.1235T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.1232T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.1232T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.1316T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.1277T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.1265T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.956T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.1232T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.956T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.887T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.887T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.1307T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.1460T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.1309T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000166447	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 1, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21520333, 28492532
SCV005056085	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 30, 2023)	unknown	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

SCV000166447

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 1, 2023)

germline

clinical testing

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

SCV005056085

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 30, 2023)

unknown

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

LOVD v.2.0: the next generation in gene variant databases.

Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT.

Hum Mutat. 2011 May;32(5):557-63. doi: 10.1002/humu.21438. Epub 2011 Feb 22.

PubMed [citation]

PMID:: 21520333

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, SCV000166447.7

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

Description

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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 135984). This missense change has been observed in individual(s) with clinical features of MUTYH-related polyposis (PMID: 21520333; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs587780745, gnomAD 0.0009%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 439 of the MUTYH protein (p.Leu439Pro).

#	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 Baylor Genetics, SCV005056085.1

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

Last Updated: Sep 29, 2024

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