NM_000038.6(APC):c.1370C>A (p.Ser457Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 14, 2023
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:: RCV001186209.14

Allele description [Variation Report for NM_000038.6(APC):c.1370C>A (p.Ser457Ter)]

NM_000038.6(APC):c.1370C>A (p.Ser457Ter)

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.1370C>A (p.Ser457Ter)

HGVS:

NC_000005.10:g.112821953C>A
NG_008481.4:g.134433C>A
NM_000038.6:c.1370C>AMANE SELECT
NM_001127510.3:c.1370C>A
NM_001127511.3:c.1316C>A
NM_001354895.2:c.1370C>A
NM_001354896.2:c.1370C>A
NM_001354897.2:c.1400C>A
NM_001354898.2:c.1295C>A
NM_001354899.2:c.1286C>A
NM_001354900.2:c.1193C>A
NM_001354901.2:c.1193C>A
NM_001354902.2:c.1097C>A
NM_001354903.2:c.1067C>A
NM_001354904.2:c.992C>A
NM_001354905.2:c.890C>A
NM_001354906.2:c.521C>A
NP_000029.2:p.Ser457Ter
NP_001120982.1:p.Ser457Ter
NP_001120983.2:p.Ser439Ter
NP_001341824.1:p.Ser457Ter
NP_001341825.1:p.Ser457Ter
NP_001341826.1:p.Ser467Ter
NP_001341827.1:p.Ser432Ter
NP_001341828.1:p.Ser429Ter
NP_001341829.1:p.Ser398Ter
NP_001341830.1:p.Ser398Ter
NP_001341831.1:p.Ser366Ter
NP_001341832.1:p.Ser356Ter
NP_001341833.1:p.Ser331Ter
NP_001341834.1:p.Ser297Ter
NP_001341835.1:p.Ser174Ter
LRG_130:g.134433C>A
NC_000005.9:g.112157650C>A
NM_000038.5:c.1370C>A
p.Ser457*

Protein change:

S174*

Links:

dbSNP: rs1060503333

NCBI 1000 Genomes Browser:

rs1060503333

Molecular consequence:

NM_000038.6:c.1370C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001127510.3:c.1370C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001127511.3:c.1316C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354895.2:c.1370C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354896.2:c.1370C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354897.2:c.1400C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354898.2:c.1295C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354899.2:c.1286C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354900.2:c.1193C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354901.2:c.1193C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354902.2:c.1097C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354903.2:c.1067C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354904.2:c.992C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354905.2:c.890C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354906.2:c.521C>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV001352561	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 11, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002696119	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 14, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20223039, 20685668, 25525159, 7959691 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001352561

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 11, 2020)

germline

clinical testing

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

SCV002696119

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 14, 2023)

germline

clinical testing

PubMed (4)
[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	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

Familial adenomatous polyposis: experience from a study of 1164 unrelated german polyposis patients.

Friedl W, Aretz S.

Hered Cancer Clin Pract. 2005 Sep 15;3(3):95-114. doi: 10.1186/1897-4287-3-3-95.

PubMed [citation]

PMID:: 20223039
PMCID:: PMC2837297

See all PubMed Citations (5)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001352561.2

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

Description

This variant changes 1 nucleotide in exon 11 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with or suspected of having familial adenomatous polyposis (PMID: 20223039, 20685668). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

#	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, SCV002696119.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.S457* pathogenic mutation (also known as c.1370C>A), located in coding exon 10 of the APC gene, results from a C to A substitution at nucleotide position 1370. This changes the amino acid from a serine to a stop codon within coding exon 10. This alteration has been reported in multiple patients with a clinical diagnosis of FAP or AFAP (Wallis YL et al. Hum. Genet., 1994 Nov;94:543-8; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114; Lagarde A et al. J. Med. Genet., 2010 Oct;47:721-2). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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: Jun 29, 2024

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