NM_000038.6(APC):c.7018A>C (p.Asn2340His) AND Hereditary cancer-predisposing syndrome

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:: RCV000582404.16

Allele description [Variation Report for NM_000038.6(APC):c.7018A>C (p.Asn2340His)]

NM_000038.6(APC):c.7018A>C (p.Asn2340His)

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.7018A>C (p.Asn2340His)

HGVS:

NC_000005.10:g.112842612A>C
NG_008481.4:g.155092A>C
NM_000038.6:c.7018A>CMANE SELECT
NM_001127510.3:c.7018A>C
NM_001127511.3:c.6964A>C
NM_001354895.2:c.7018A>C
NM_001354896.2:c.7072A>C
NM_001354897.2:c.7048A>C
NM_001354898.2:c.6943A>C
NM_001354899.2:c.6934A>C
NM_001354900.2:c.6895A>C
NM_001354901.2:c.6841A>C
NM_001354902.2:c.6745A>C
NM_001354903.2:c.6715A>C
NM_001354904.2:c.6640A>C
NM_001354905.2:c.6538A>C
NM_001354906.2:c.6169A>C
NP_000029.2:p.Asn2340His
NP_001120982.1:p.Asn2340His
NP_001120983.2:p.Asn2322His
NP_001341824.1:p.Asn2340His
NP_001341825.1:p.Asn2358His
NP_001341826.1:p.Asn2350His
NP_001341827.1:p.Asn2315His
NP_001341828.1:p.Asn2312His
NP_001341829.1:p.Asn2299His
NP_001341830.1:p.Asn2281His
NP_001341831.1:p.Asn2249His
NP_001341832.1:p.Asn2239His
NP_001341833.1:p.Asn2214His
NP_001341834.1:p.Asn2180His
NP_001341835.1:p.Asn2057His
LRG_130:g.155092A>C
NC_000005.9:g.112178309A>C
NM_000038.5:c.7018A>C

Protein change:

N2057H

Links:

dbSNP: rs748940586

NCBI 1000 Genomes Browser:

rs748940586

Molecular consequence:

NM_000038.6:c.7018A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.7018A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.6964A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.7018A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.7072A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.7048A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.6943A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.6934A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.6895A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.6841A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.6745A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.6715A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.6640A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.6538A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.6169A>C - 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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Nicotinate phosphoribosyltransferase domain containing 1 [Mus musculus]
Nicotinate phosphoribosyltransferase domain containing 1 [Mus musculus]
gi|37589273|gb|AAH58800.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000687107	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 2, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001188213	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Nov 30, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25559809, 32992489 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000687107

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 2, 2021)

germline

clinical testing

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

SCV001188213

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Nov 30, 2023)

germline

clinical testing

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

Citation Link

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

Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing.

Chubb D, Broderick P, Frampton M, Kinnersley B, Sherborne A, Penegar S, Lloyd A, Ma YP, Dobbins SE, Houlston RS.

J Clin Oncol. 2015 Feb 10;33(5):426-32. doi: 10.1200/JCO.2014.56.5689. Epub 2015 Jan 5.

PubMed [citation]

PMID:: 25559809

See all PubMed Citations (3)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000687107.4

#	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 asparagine with histidine at codon 2340 of the APC protein. Computational prediction tool 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 individuals affected with colon cancer (PMID: 25559809). This variant has been identified in 4/250218 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 Ambry Genetics, SCV001188213.4

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

Description

The p.N2340H variant (also known as c.7018A>C), located in coding exon 15 of the APC gene, results from an A to C substitution at nucleotide position 7018. The asparagine at codon 2340 is replaced by histidine, an amino acid with similar properties. This variant was observed in 1/626 individuals with early-onset familial colorectal cancer cases, who had germline genetic testing for colon cancer associated genes; this 55 year old female had proximal colon cancer and a maternal aunt with colorectal cancer at age 62 (Chubb D et al. J. Clin. Oncol. 2015 Feb; 33(5):426-32). This alteration was also reported in a cohort of elderly cancer-free individuals (Zheng G et al. Cancers (Basel), 2020 Sep;12:). 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

Last Updated: Oct 13, 2024

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