NM_000038.6(APC):c.817A>G (p.Thr273Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Nov 4, 2022
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:: RCV001184707.14

Allele description [Variation Report for NM_000038.6(APC):c.817A>G (p.Thr273Ala)]

NM_000038.6(APC):c.817A>G (p.Thr273Ala)

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.817A>G (p.Thr273Ala)

HGVS:

NC_000005.10:g.112801366A>G
NG_008481.4:g.113846A>G
NM_000038.6:c.817A>GMANE SELECT
NM_001127510.3:c.817A>G
NM_001127511.3:c.763A>G
NM_001354895.2:c.817A>G
NM_001354896.2:c.817A>G
NM_001354897.2:c.847A>G
NM_001354898.2:c.742A>G
NM_001354899.2:c.733A>G
NM_001354900.2:c.640A>G
NM_001354901.2:c.640A>G
NM_001354902.2:c.847A>G
NM_001354903.2:c.817A>G
NM_001354904.2:c.742A>G
NM_001354905.2:c.640A>G
NM_001354906.2:c.-219A>G
NP_000029.2:p.Thr273Ala
NP_001120982.1:p.Thr273Ala
NP_001120983.2:p.Thr255Ala
NP_001341824.1:p.Thr273Ala
NP_001341825.1:p.Thr273Ala
NP_001341826.1:p.Thr283Ala
NP_001341827.1:p.Thr248Ala
NP_001341828.1:p.Thr245Ala
NP_001341829.1:p.Thr214Ala
NP_001341830.1:p.Thr214Ala
NP_001341831.1:p.Thr283Ala
NP_001341832.1:p.Thr273Ala
NP_001341833.1:p.Thr248Ala
NP_001341834.1:p.Thr214Ala
LRG_130t1:c.817A>G
LRG_130:g.113846A>G
NC_000005.9:g.112137063A>G
NM_000038.4:c.817A>G
NM_000038.5:c.817A>G

Protein change:

T214A

Links:

dbSNP: rs770768719

NCBI 1000 Genomes Browser:

rs770768719

Molecular consequence:

NM_001354906.2:c.-219A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000038.6:c.817A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.817A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.763A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.817A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.817A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.847A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.742A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.733A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.640A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.640A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.847A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.817A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.742A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.640A>G - 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
SCV001350743	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 16, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002531626	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Apr 30, 2021)	germline	curation	Citation Link,
SCV002680456	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Nov 4, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001350743

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 16, 2021)

germline

clinical testing

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

SCV002531626

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Apr 30, 2021)

germline

curation

Citation Link,

SCV002680456

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Nov 4, 2022)

germline

clinical testing

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, 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

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001350743.2

#	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 threonine with alanine at codon 273 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/250928 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, SCV002531626.1

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

#	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, SCV002680456.3

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

Description

The p.T273A variant (also known as c.817A>G), located in coding exon 7 of the APC gene, results from an A to G substitution at nucleotide position 817. The threonine at codon 273 is replaced by alanine, an amino acid with similar properties. This amino acid position is not 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: May 1, 2024

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