NM_000038.6(APC):c.5939A>G (p.Asn1980Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 5, 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:: RCV002355908.3

Allele description [Variation Report for NM_000038.6(APC):c.5939A>G (p.Asn1980Ser)]

NM_000038.6(APC):c.5939A>G (p.Asn1980Ser)

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.5939A>G (p.Asn1980Ser)

HGVS:

NC_000005.10:g.112841533A>G
NG_008481.4:g.154013A>G
NM_000038.6:c.5939A>GMANE SELECT
NM_001127510.3:c.5939A>G
NM_001127511.3:c.5885A>G
NM_001354895.2:c.5939A>G
NM_001354896.2:c.5993A>G
NM_001354897.2:c.5969A>G
NM_001354898.2:c.5864A>G
NM_001354899.2:c.5855A>G
NM_001354900.2:c.5816A>G
NM_001354901.2:c.5762A>G
NM_001354902.2:c.5666A>G
NM_001354903.2:c.5636A>G
NM_001354904.2:c.5561A>G
NM_001354905.2:c.5459A>G
NM_001354906.2:c.5090A>G
NM_001407446.1:c.6023A>G
NM_001407447.1:c.5993A>G
NM_001407448.1:c.5993A>G
NM_001407449.1:c.5993A>G
NM_001407450.1:c.5939A>G
NM_001407451.1:c.5918A>G
NM_001407452.1:c.5909A>G
NM_001407453.1:c.5762A>G
NM_001407454.1:c.5690A>G
NM_001407455.1:c.5690A>G
NM_001407456.1:c.5690A>G
NM_001407457.1:c.5690A>G
NM_001407458.1:c.5636A>G
NM_001407459.1:c.5636A>G
NM_001407460.1:c.5636A>G
NM_001407467.1:c.5552A>G
NM_001407469.1:c.5552A>G
NM_001407470.1:c.5090A>G
NM_001407471.1:c.4787A>G
NM_001407472.1:c.4787A>G
NP_000029.2:p.Asn1980Ser
NP_000029.2:p.Asn1980Ser
NP_001120982.1:p.Asn1980Ser
NP_001120982.1:p.Asn1980Ser
NP_001120983.1:p.Asn1980Ser
NP_001120983.2:p.Asn1962Ser
NP_001341824.1:p.Asn1980Ser
NP_001341825.1:p.Asn1998Ser
NP_001341826.1:p.Asn1990Ser
NP_001341827.1:p.Asn1955Ser
NP_001341828.1:p.Asn1952Ser
NP_001341829.1:p.Asn1939Ser
NP_001341830.1:p.Asn1921Ser
NP_001341831.1:p.Asn1889Ser
NP_001341832.1:p.Asn1879Ser
NP_001341833.1:p.Asn1854Ser
NP_001341834.1:p.Asn1820Ser
NP_001341835.1:p.Asn1697Ser
NP_001394375.1:p.Asn2008Ser
NP_001394376.1:p.Asn1998Ser
NP_001394377.1:p.Asn1998Ser
NP_001394378.1:p.Asn1998Ser
NP_001394379.1:p.Asn1980Ser
NP_001394380.1:p.Asn1973Ser
NP_001394381.1:p.Asn1970Ser
NP_001394382.1:p.Asn1921Ser
NP_001394383.1:p.Asn1897Ser
NP_001394384.1:p.Asn1897Ser
NP_001394385.1:p.Asn1897Ser
NP_001394386.1:p.Asn1897Ser
NP_001394387.1:p.Asn1879Ser
NP_001394388.1:p.Asn1879Ser
NP_001394389.1:p.Asn1879Ser
NP_001394396.1:p.Asn1851Ser
NP_001394398.1:p.Asn1851Ser
NP_001394399.1:p.Asn1697Ser
NP_001394400.1:p.Asn1596Ser
NP_001394401.1:p.Asn1596Ser
LRG_130t1:c.5939A>G
LRG_130t2:c.5939A>G
LRG_130t3:c.5939A>G
LRG_130:g.154013A>G
LRG_130p1:p.Asn1980Ser
LRG_130p2:p.Asn1980Ser
LRG_130p3:p.Asn1980Ser
NC_000005.9:g.112177230A>G
NM_000038.4:c.5939A>G
NM_000038.5:c.5939A>G
NM_001127510.1:c.5939A>G
NM_001127511.1:c.5939A>G
NR_176365.1:n.5774A>G
NR_176366.1:n.6193A>G

Protein change:

N1596S

Molecular consequence:

NM_000038.6:c.5939A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.5939A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.5885A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.5939A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.5993A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.5969A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.5864A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.5855A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.5816A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.5762A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.5666A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.5636A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.5561A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.5459A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.5090A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407446.1:c.6023A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407447.1:c.5993A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407448.1:c.5993A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407449.1:c.5993A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407450.1:c.5939A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407451.1:c.5918A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407452.1:c.5909A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407453.1:c.5762A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407454.1:c.5690A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407455.1:c.5690A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407456.1:c.5690A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407457.1:c.5690A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407458.1:c.5636A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407459.1:c.5636A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407460.1:c.5636A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407467.1:c.5552A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407469.1:c.5552A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407470.1:c.5090A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407471.1:c.4787A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407472.1:c.4787A>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
SCV002649936	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Sep 24, 2022)	germline	clinical testing	Citation Link,
SCV004357361	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 5, 2023)	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

SCV002649936

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Sep 24, 2022)

germline

clinical testing

Citation Link,

SCV004357361

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 5, 2023)

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, SCV002649936.2

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

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, SCV004357361.1

#	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 asparagine with serine at codon 1980 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 APC-related disorders in the literature. This variant has been identified in 3/250476 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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