NM_000038.6(APC):c.4372C>T (p.Pro1458Ser) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 18, 2024
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:: RCV000034415.24

Allele description [Variation Report for NM_000038.6(APC):c.4372C>T (p.Pro1458Ser)]

NM_000038.6(APC):c.4372C>T (p.Pro1458Ser)

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.4372C>T (p.Pro1458Ser)

Other names:

p.P1458S:CCT>TCT

HGVS:

NC_000005.10:g.112839966C>T
NG_008481.4:g.152446C>T
NM_000038.6:c.4372C>TMANE SELECT
NM_001127510.3:c.4372C>T
NM_001127511.3:c.4318C>T
NM_001354895.2:c.4372C>T
NM_001354896.2:c.4426C>T
NM_001354897.2:c.4402C>T
NM_001354898.2:c.4297C>T
NM_001354899.2:c.4288C>T
NM_001354900.2:c.4249C>T
NM_001354901.2:c.4195C>T
NM_001354902.2:c.4099C>T
NM_001354903.2:c.4069C>T
NM_001354904.2:c.3994C>T
NM_001354905.2:c.3892C>T
NM_001354906.2:c.3523C>T
NP_000029.2:p.Pro1458Ser
NP_001120982.1:p.Pro1458Ser
NP_001120983.2:p.Pro1440Ser
NP_001341824.1:p.Pro1458Ser
NP_001341825.1:p.Pro1476Ser
NP_001341826.1:p.Pro1468Ser
NP_001341827.1:p.Pro1433Ser
NP_001341828.1:p.Pro1430Ser
NP_001341829.1:p.Pro1417Ser
NP_001341830.1:p.Pro1399Ser
NP_001341831.1:p.Pro1367Ser
NP_001341832.1:p.Pro1357Ser
NP_001341833.1:p.Pro1332Ser
NP_001341834.1:p.Pro1298Ser
NP_001341835.1:p.Pro1175Ser
LRG_130:g.152446C>T
NC_000005.9:g.112175663C>T
NM_000038.5:c.4372C>T
p.P1458S

Protein change:

P1175S

Links:

dbSNP: rs143796828

NCBI 1000 Genomes Browser:

rs143796828

Molecular consequence:

NM_000038.6:c.4372C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.4372C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.4318C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.4372C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.4426C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.4402C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.4297C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.4288C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.4249C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.4195C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.4099C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.4069C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.3994C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.3892C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.3523C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000043127	Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq	no assertion criteria provided	variant of unknown significance (Jul 13, 2012)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000209525	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Feb 1, 2023)	germline	clinical testing	Citation Link,
SCV005624466	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Jan 18, 2024)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 28726808, 22703879, 18199528, 31240473, 26320869, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000043127

Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq

no assertion criteria provided

variant of unknown significance
(Jul 13, 2012)

germline

research

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

SCV000209525

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Feb 1, 2023)

germline

clinical testing

Citation Link,

SCV005624466

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Jan 18, 2024)

unknown

clinical testing

PubMed (6)
[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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	1	not provided	not provided	572	not provided	research

Citations

PubMed

Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history.

Chaffee KG, Oberg AL, McWilliams RR, Majithia N, Allen BA, Kidd J, Singh N, Hartman AR, Wenstrup RJ, Petersen GM.

Genet Med. 2018 Jan;20(1):119-127. doi: 10.1038/gim.2017.85. Epub 2017 Jul 20.

PubMed [citation]

PMID:: 28726808
PMCID:: PMC5760284

Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.

Johnston JJ, Rubinstein WS, Facio FM, Ng D, Singh LN, Teer JK, Mullikin JC, Biesecker LG.

Am J Hum Genet. 2012 Jul 13;91(1):97-108. doi: 10.1016/j.ajhg.2012.05.021. Epub 2012 Jun 14.

PubMed [citation]

PMID:: 22703879
PMCID:: PMC3397257

See all PubMed Citations (6)

Details of each submission

From Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq, SCV000043127.1

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

Description

The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See PubMed ID:22703879 for details.

Description

Converted during submission to Uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	572	not provided	discovery		1	not provided	not provided	not provided

From GeneDx, SCV000209525.16

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

Description

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a healthy control individual and in an individual with atherosclerosis in published literature (Azzopardi et al., 2008; Johnston et al., 2012); This variant is associated with the following publications: (PMID: 18199528, 22703879, 26320869)

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV005624466.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The APC c.4372C>T (p.Pro1458Ser) variant has been reported in the published literature along with other variants in individuals affected with bladder cancer (PMID: 26320869 (2015)), pancreatic cancer (PMID: 28726808 (2018)), and enchondromas (PMID: 31240473 (2019)). It was also detected in reportedly healthy individuals (PMID: 18199528 (2008)). The frequency of this variant in the general population, 0.00017 (6/35422 chromosomes in Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

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

Last Updated: Feb 25, 2025

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