NM_000038.6(APC):c.669A>C (p.Gln223His) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Apr 3, 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:: RCV000163884.16

Allele description [Variation Report for NM_000038.6(APC):c.669A>C (p.Gln223His)]

NM_000038.6(APC):c.669A>C (p.Gln223His)

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.669A>C (p.Gln223His)

HGVS:

NC_000005.10:g.112792469A>C
NG_008481.4:g.104949A>C
NM_000038.6:c.669A>CMANE SELECT
NM_001127510.3:c.669A>C
NM_001127511.3:c.676-8810A>C
NM_001354895.2:c.669A>C
NM_001354896.2:c.669A>C
NM_001354897.2:c.699A>C
NM_001354898.2:c.594A>C
NM_001354899.2:c.646-8810A>C
NM_001354900.2:c.492A>C
NM_001354901.2:c.492A>C
NM_001354902.2:c.699A>C
NM_001354903.2:c.669A>C
NM_001354904.2:c.594A>C
NM_001354905.2:c.492A>C
NM_001354906.2:c.-367A>C
NP_000029.2:p.Gln223His
NP_001120982.1:p.Gln223His
NP_001341824.1:p.Gln223His
NP_001341825.1:p.Gln223His
NP_001341826.1:p.Gln233His
NP_001341827.1:p.Gln198His
NP_001341829.1:p.Gln164His
NP_001341830.1:p.Gln164His
NP_001341831.1:p.Gln233His
NP_001341832.1:p.Gln223His
NP_001341833.1:p.Gln198His
NP_001341834.1:p.Gln164His
LRG_130:g.104949A>C
NC_000005.9:g.112128166A>C
NM_000038.5:c.669A>C
p.Q223H

Protein change:

Q164H

Links:

dbSNP: rs769482880

NCBI 1000 Genomes Browser:

rs769482880

Molecular consequence:

NM_001354906.2:c.-367A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001127511.3:c.676-8810A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001354899.2:c.646-8810A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000038.6:c.669A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.669A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.669A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.669A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.699A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.594A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.492A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.492A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.699A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.669A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.594A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.492A>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

Recent activity

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transmembrane protein [Mycobacterium tuberculosis H37Rv]
transmembrane protein [Mycobacterium tuberculosis H37Rv]
gi|57116956|ref|NP_216722.2|

Protein
Palmar Plate
Palmar Plate
A thick, fibrocartilaginous ligament at the METACARPOPHALANGEAL JOINT of the hand.<br/>Year introduced: 2016

MeSH
D053401 (1)
MeSH
Saccharomyces cerevisiae S288C 1,3-beta-D-glucan synthase (FKS1), partial mRNA
Saccharomyces cerevisiae S288C 1,3-beta-D-glucan synthase (FKS1), partial mRNA
gi|296146866|ref|NM_001182231.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000214474	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Sep 30, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000687091	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 3, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23159591, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000214474

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Sep 30, 2020)

germline

clinical testing

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

Citation Link,

SCV000687091

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 3, 2023)

germline

clinical testing

PubMed (2)
[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

APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests.

Kerr SE, Thomas CB, Thibodeau SN, Ferber MJ, Halling KC.

J Mol Diagn. 2013 Jan;15(1):31-43. doi: 10.1016/j.jmoldx.2012.07.005. Epub 2012 Nov 14. Review.

PubMed [citation]

PMID:: 23159591

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, SCV000214474.7

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

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000687091.6

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

Description

This missense variant replaces glutamine with histidine at codon 223 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual being evaluated for familial adenomatous polyposis (PMID: 23159591). This variant has been identified in 4/251000 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: Sep 16, 2024

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