NM_000038.6(APC):c.7402T>C (p.Ser2468Pro) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: May 16, 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:: RCV000163734.21

Allele description [Variation Report for NM_000038.6(APC):c.7402T>C (p.Ser2468Pro)]

NM_000038.6(APC):c.7402T>C (p.Ser2468Pro)

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.7402T>C (p.Ser2468Pro)

HGVS:

NC_000005.10:g.112842996T>C
NG_008481.4:g.155476T>C
NM_000038.6:c.7402T>CMANE SELECT
NM_001127510.3:c.7402T>C
NM_001127511.3:c.7348T>C
NM_001354895.2:c.7402T>C
NM_001354896.2:c.7456T>C
NM_001354897.2:c.7432T>C
NM_001354898.2:c.7327T>C
NM_001354899.2:c.7318T>C
NM_001354900.2:c.7279T>C
NM_001354901.2:c.7225T>C
NM_001354902.2:c.7129T>C
NM_001354903.2:c.7099T>C
NM_001354904.2:c.7024T>C
NM_001354905.2:c.6922T>C
NM_001354906.2:c.6553T>C
NP_000029.2:p.Ser2468Pro
NP_001120982.1:p.Ser2468Pro
NP_001120983.2:p.Ser2450Pro
NP_001341824.1:p.Ser2468Pro
NP_001341825.1:p.Ser2486Pro
NP_001341826.1:p.Ser2478Pro
NP_001341827.1:p.Ser2443Pro
NP_001341828.1:p.Ser2440Pro
NP_001341829.1:p.Ser2427Pro
NP_001341830.1:p.Ser2409Pro
NP_001341831.1:p.Ser2377Pro
NP_001341832.1:p.Ser2367Pro
NP_001341833.1:p.Ser2342Pro
NP_001341834.1:p.Ser2308Pro
NP_001341835.1:p.Ser2185Pro
LRG_130:g.155476T>C
NC_000005.9:g.112178693T>C
NM_000038.4:c.7402T>C
NM_000038.5:c.7402T>C
p.S2468P

Protein change:

S2185P

Links:

dbSNP: rs375586273

NCBI 1000 Genomes Browser:

rs375586273

Molecular consequence:

NM_000038.6:c.7402T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.7402T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.7348T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.7402T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.7456T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.7432T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.7327T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.7318T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.7279T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.7225T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.7129T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.7099T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.7024T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.6922T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.6553T>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000214309	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 16, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25186627, 27696107 Citation Link,
SCV000687125	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 16, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25186627, 27696107, 25741868
SCV002527601	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (May 17, 2021)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 25186627, 27696107 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000214309

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 16, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000687125

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 16, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002527601

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(May 17, 2021)

germline

curation

PubMed (2)
[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, 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

Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.

Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, Timms K, Garber JE, Herold C, Ellisen L, Krejdovsky J, DeLeonardis K, Sedgwick K, Soltis K, Roa B, Wenstrup RJ, Hartman AR.

Cancer. 2015 Jan 1;121(1):25-33. doi: 10.1002/cncr.29010. Epub 2014 Sep 3.

PubMed [citation]

PMID:: 25186627

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000214309.8

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

Description

The p.S2468P variant (also known as c.7402T>C), located in coding exon 15 of the APC gene, results from a T to C substitution at nucleotide position 7402. The serine at codon 2468 is replaced by proline, an amino acid with similar properties. This alteration was detected on a 25-gene panel test in a woman of Western/Northern European ancestry with a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). This alteration was also reported in conjunction with a PMS2 truncating mutation in a patient with endometrial cancer diagnosed at age 50 and MSI-H, MSH6-absent ascending colorectal cancer diagnosed at age 80. This individual did not have colon polyps and met Amsterdam criteria (Rohlin A et al. Fam. Cancer. 2017 Apr;16:195-203). This amino acid position is highly 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

From Color Diagnostics, LLC DBA Color Health, SCV000687125.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces serine with proline at codon 2468 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 been observed in an individual affected with breast cancer (PMID: 25186627) and in an individual affected with colorectal cancer, who also carried a pathogenic PMS2 variant that could explain the observed phenotype (PMID: 27696107). This variant has been identified in 3/245882 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, SCV002527601.1

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

#	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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