NM_000038.6(APC):c.7589G>A (p.Arg2530Gln) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 8, 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:: RCV000222733.17

Allele description [Variation Report for NM_000038.6(APC):c.7589G>A (p.Arg2530Gln)]

NM_000038.6(APC):c.7589G>A (p.Arg2530Gln)

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.7589G>A (p.Arg2530Gln)

HGVS:

NC_000005.10:g.112843183G>A
NG_008481.4:g.155663G>A
NM_000038.6:c.7589G>AMANE SELECT
NM_001127510.3:c.7589G>A
NM_001127511.3:c.7535G>A
NM_001354895.2:c.7589G>A
NM_001354896.2:c.7643G>A
NM_001354897.2:c.7619G>A
NM_001354898.2:c.7514G>A
NM_001354899.2:c.7505G>A
NM_001354900.2:c.7466G>A
NM_001354901.2:c.7412G>A
NM_001354902.2:c.7316G>A
NM_001354903.2:c.7286G>A
NM_001354904.2:c.7211G>A
NM_001354905.2:c.7109G>A
NM_001354906.2:c.6740G>A
NP_000029.2:p.Arg2530Gln
NP_001120982.1:p.Arg2530Gln
NP_001120983.2:p.Arg2512Gln
NP_001341824.1:p.Arg2530Gln
NP_001341825.1:p.Arg2548Gln
NP_001341826.1:p.Arg2540Gln
NP_001341827.1:p.Arg2505Gln
NP_001341828.1:p.Arg2502Gln
NP_001341829.1:p.Arg2489Gln
NP_001341830.1:p.Arg2471Gln
NP_001341831.1:p.Arg2439Gln
NP_001341832.1:p.Arg2429Gln
NP_001341833.1:p.Arg2404Gln
NP_001341834.1:p.Arg2370Gln
NP_001341835.1:p.Arg2247Gln
LRG_130:g.155663G>A
NC_000005.9:g.112178880G>A
NM_000038.5:c.7589G>A

Protein change:

R2247Q

Links:

dbSNP: rs587778043

NCBI 1000 Genomes Browser:

rs587778043

Molecular consequence:

NM_000038.6:c.7589G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.7589G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.7535G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.7589G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.7643G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.7619G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.7514G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.7505G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.7466G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.7412G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.7316G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.7286G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.7211G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.7109G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.6740G>A - 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
SCV000276417	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 25, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24728327, 26976419, 29192238, 32658311 Citation Link,
SCV000681880	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 8, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24728327, 26976419, 29192238, 32658311, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000276417

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jan 25, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000681880

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 8, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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

Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.

Bodian DL, McCutcheon JN, Kothiyal P, Huddleston KC, Iyer RK, Vockley JG, Niederhuber JE.

PLoS One. 2014;9(4):e94554. doi: 10.1371/journal.pone.0094554.

PubMed [citation]

PMID:: 24728327
PMCID:: PMC3984285

Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer.

Tung N, Lin NU, Kidd J, Allen BA, Singh N, Wenstrup RJ, Hartman AR, Winer EP, Garber JE.

J Clin Oncol. 2016 May 1;34(13):1460-8. doi: 10.1200/JCO.2015.65.0747. Epub 2016 Mar 14.

PubMed [citation]

PMID:: 26976419
PMCID:: PMC4872307

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000276417.7

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

Description

The p.R2530Q variant (also known as c.7589G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 7589. The arginine at codon 2530 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). This alteration was observed in a Japanese population cohort of 2049 individuals who underwent whole-genome sequencing (Yamaguchi-Kabata Y et al. J Hum Genet, 2018 Feb;63:213-230). This variant has also been identified in healthy cohorts without a known history of cancer (Bodian DL et al. PLoS One, 2014 Apr;9:e94554; Akcay IM et al. Int J Cancer, 2021 01;148:285-295).This amino acid position is highly 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, SCV000681880.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces arginine with glutamine at codon 2530 of the APC protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. 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 breast cancer (PMID: 26976419), but also in healthy control individuals (PMID: 24728327, 29192238, 32658311). This variant has also been identified in 1/250692 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: Jun 29, 2024

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