NM_000038.6(APC):c.8462A>G (p.Asp2821Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: May 10, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000567493.11

Allele description [Variation Report for NM_000038.6(APC):c.8462A>G (p.Asp2821Gly)]

NM_000038.6(APC):c.8462A>G (p.Asp2821Gly)

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.8462A>G (p.Asp2821Gly)

HGVS:

NC_000005.10:g.112844056A>G
NG_008481.4:g.156536A>G
NM_000038.6:c.8462A>GMANE SELECT
NM_001127510.3:c.8462A>G
NM_001127511.3:c.8408A>G
NM_001354895.2:c.8462A>G
NM_001354896.2:c.8516A>G
NM_001354897.2:c.8492A>G
NM_001354898.2:c.8387A>G
NM_001354899.2:c.8378A>G
NM_001354900.2:c.8339A>G
NM_001354901.2:c.8285A>G
NM_001354902.2:c.8189A>G
NM_001354903.2:c.8159A>G
NM_001354904.2:c.8084A>G
NM_001354905.2:c.7982A>G
NM_001354906.2:c.7613A>G
NP_000029.2:p.Asp2821Gly
NP_001120982.1:p.Asp2821Gly
NP_001120983.2:p.Asp2803Gly
NP_001341824.1:p.Asp2821Gly
NP_001341825.1:p.Asp2839Gly
NP_001341826.1:p.Asp2831Gly
NP_001341827.1:p.Asp2796Gly
NP_001341828.1:p.Asp2793Gly
NP_001341829.1:p.Asp2780Gly
NP_001341830.1:p.Asp2762Gly
NP_001341831.1:p.Asp2730Gly
NP_001341832.1:p.Asp2720Gly
NP_001341833.1:p.Asp2695Gly
NP_001341834.1:p.Asp2661Gly
NP_001341835.1:p.Asp2538Gly
LRG_130t1:c.8462A>G
LRG_130:g.156536A>G
NC_000005.9:g.112179753A>G
NM_000038.4:c.8462A>G
NM_000038.5:c.8462A>G

Protein change:

D2538G

Links:

dbSNP: rs780049836

NCBI 1000 Genomes Browser:

rs780049836

Molecular consequence:

NM_000038.6:c.8462A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.8462A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.8408A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.8462A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.8516A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.8492A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.8387A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.8378A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.8339A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.8285A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.8189A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.8159A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.8084A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.7982A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.7613A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000667248	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Benign (Mar 16, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26580448, 26976419 Citation Link,
SCV000903243	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 10, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26580448, 26976419, 25741868
SCV002527013	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Aug 7, 2021)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 26976419, 26580448 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000667248

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Benign
(Mar 16, 2021)

germline

clinical testing

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

Citation Link,

SCV000903243

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 10, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002527013

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Aug 7, 2021)

germline

curation

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	1	not provided	not provided	1	not provided	clinical testing, curation

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

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 (3)

Details of each submission

From Ambry Genetics, SCV000667248.4

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

Description

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000903243.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces aspartic acid with glycine at codon 2821 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26976419) and in an individual affected with acute lymphoblastic leukemia (PMID: 26580448). This variant has been identified in 10/271548 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 Sema4, Sema4, SCV002527013.1

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

#	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: Mar 5, 2024

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