NM_000038.6(APC):c.7085G>C (p.Gly2362Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 8, 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:: RCV000570255.15

Allele description [Variation Report for NM_000038.6(APC):c.7085G>C (p.Gly2362Ala)]

NM_000038.6(APC):c.7085G>C (p.Gly2362Ala)

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.7085G>C (p.Gly2362Ala)

HGVS:

NC_000005.10:g.112842679G>C
NG_008481.4:g.155159G>C
NM_000038.6:c.7085G>CMANE SELECT
NM_001127510.3:c.7085G>C
NM_001127511.3:c.7031G>C
NM_001354895.2:c.7085G>C
NM_001354896.2:c.7139G>C
NM_001354897.2:c.7115G>C
NM_001354898.2:c.7010G>C
NM_001354899.2:c.7001G>C
NM_001354900.2:c.6962G>C
NM_001354901.2:c.6908G>C
NM_001354902.2:c.6812G>C
NM_001354903.2:c.6782G>C
NM_001354904.2:c.6707G>C
NM_001354905.2:c.6605G>C
NM_001354906.2:c.6236G>C
NP_000029.2:p.Gly2362Ala
NP_001120982.1:p.Gly2362Ala
NP_001120983.2:p.Gly2344Ala
NP_001341824.1:p.Gly2362Ala
NP_001341825.1:p.Gly2380Ala
NP_001341826.1:p.Gly2372Ala
NP_001341827.1:p.Gly2337Ala
NP_001341828.1:p.Gly2334Ala
NP_001341829.1:p.Gly2321Ala
NP_001341830.1:p.Gly2303Ala
NP_001341831.1:p.Gly2271Ala
NP_001341832.1:p.Gly2261Ala
NP_001341833.1:p.Gly2236Ala
NP_001341834.1:p.Gly2202Ala
NP_001341835.1:p.Gly2079Ala
LRG_130:g.155159G>C
NC_000005.9:g.112178376G>C
NM_000038.5:c.7085G>C

Protein change:

G2079A

Links:

dbSNP: rs756740976

NCBI 1000 Genomes Browser:

rs756740976

Molecular consequence:

NM_000038.6:c.7085G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.7085G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.7031G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.7085G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.7139G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.7115G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.7010G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.7001G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.6962G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.6908G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.6812G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.6782G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.6707G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.6605G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.6236G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000667735	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 8, 2024)	germline	clinical testing	Citation Link,
SCV001353805	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2020)	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

SCV000667735

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 8, 2024)

germline

clinical testing

Citation Link,

SCV001353805

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 1, 2020)

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, SCV000667735.6

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

Description

The p.G2362A variant (also known as c.7085G>C), located in coding exon 15 of the APC gene, results from a G to C substitution at nucleotide position 7085. The glycine at codon 2362 is replaced by alanine, an amino acid with similar properties. Missense alterations in APC are not a common cause of disease (Spier I et al. Genet Med. 2024 Feb;26(2):100992). This amino acid position is well conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the available evidence, the clinical significance of this variant 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, SCV001353805.2

#	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 glycine with alanine at codon 2362 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/249428 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: Oct 26, 2024

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