NM_000038.6(APC):c.5236A>G (p.Ile1746Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 18, 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:: RCV000164711.18

Allele description [Variation Report for NM_000038.6(APC):c.5236A>G (p.Ile1746Val)]

NM_000038.6(APC):c.5236A>G (p.Ile1746Val)

Gene:

APC:APC regulator of WNT signaling pathway [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q22.2

Genomic location:

Preferred name:

NM_000038.6(APC):c.5236A>G (p.Ile1746Val)

HGVS:

NC_000005.10:g.112840830A>G
NG_008481.4:g.153310A>G
NM_000038.6:c.5236A>GMANE SELECT
NM_001127510.3:c.5236A>G
NM_001127511.3:c.5182A>G
NM_001354895.2:c.5236A>G
NM_001354896.2:c.5290A>G
NM_001354897.2:c.5266A>G
NM_001354898.2:c.5161A>G
NM_001354899.2:c.5152A>G
NM_001354900.2:c.5113A>G
NM_001354901.2:c.5059A>G
NM_001354902.2:c.4963A>G
NM_001354903.2:c.4933A>G
NM_001354904.2:c.4858A>G
NM_001354905.2:c.4756A>G
NM_001354906.2:c.4387A>G
NP_000029.2:p.Ile1746Val
NP_001120982.1:p.Ile1746Val
NP_001120983.2:p.Ile1728Val
NP_001341824.1:p.Ile1746Val
NP_001341825.1:p.Ile1764Val
NP_001341826.1:p.Ile1756Val
NP_001341827.1:p.Ile1721Val
NP_001341828.1:p.Ile1718Val
NP_001341829.1:p.Ile1705Val
NP_001341830.1:p.Ile1687Val
NP_001341831.1:p.Ile1655Val
NP_001341832.1:p.Ile1645Val
NP_001341833.1:p.Ile1620Val
NP_001341834.1:p.Ile1586Val
NP_001341835.1:p.Ile1463Val
LRG_130:g.153310A>G
NC_000005.9:g.112176527A>G
NM_000038.5:c.5236A>G
p.I1746V

Protein change:

I1463V

Links:

dbSNP: rs786202076

NCBI 1000 Genomes Browser:

rs786202076

Molecular consequence:

NM_000038.6:c.5236A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.5236A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.5182A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.5236A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.5290A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.5266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.5161A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.5152A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.5113A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.5059A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.4963A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.4933A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.4858A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.4756A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.4387A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; 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
SCV000215381	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Oct 11, 2022)	germline	clinical testing	Citation Link,
SCV000687008	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 18, 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

SCV000215381

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Oct 11, 2022)

germline

clinical testing

Citation Link,

SCV000687008

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 18, 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	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

Details of each submission

From Ambry Genetics, SCV000215381.7

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

Description

The p.I1746V variant (also known as c.5236A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 5236. The isoleucine at codon 1746 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. 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, SCV000687008.4

#	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 isoleucine with valine at codon 1746 of the APC protein. 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 impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with attenuated form of familial adenomatous polyposis (Lin et al. poster# 1213, American Journal of Gastroenterology 2012). This variant has been identified in 1/31410 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

Last Updated: Nov 10, 2024

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