NM_000038.6(APC):c.7793C>T (p.Thr2598Ile) AND Familial adenomatous polyposis 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 15, 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:: RCV000987587.14

Allele description [Variation Report for NM_000038.6(APC):c.7793C>T (p.Thr2598Ile)]

NM_000038.6(APC):c.7793C>T (p.Thr2598Ile)

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.7793C>T (p.Thr2598Ile)

HGVS:

NC_000005.10:g.112843387C>T
NG_008481.4:g.155867C>T
NM_000038.6:c.7793C>TMANE SELECT
NM_001127510.3:c.7793C>T
NM_001127511.3:c.7739C>T
NM_001354895.2:c.7793C>T
NM_001354896.2:c.7847C>T
NM_001354897.2:c.7823C>T
NM_001354898.2:c.7718C>T
NM_001354899.2:c.7709C>T
NM_001354900.2:c.7670C>T
NM_001354901.2:c.7616C>T
NM_001354902.2:c.7520C>T
NM_001354903.2:c.7490C>T
NM_001354904.2:c.7415C>T
NM_001354905.2:c.7313C>T
NM_001354906.2:c.6944C>T
NP_000029.2:p.Thr2598Ile
NP_001120982.1:p.Thr2598Ile
NP_001120983.2:p.Thr2580Ile
NP_001341824.1:p.Thr2598Ile
NP_001341825.1:p.Thr2616Ile
NP_001341826.1:p.Thr2608Ile
NP_001341827.1:p.Thr2573Ile
NP_001341828.1:p.Thr2570Ile
NP_001341829.1:p.Thr2557Ile
NP_001341830.1:p.Thr2539Ile
NP_001341831.1:p.Thr2507Ile
NP_001341832.1:p.Thr2497Ile
NP_001341833.1:p.Thr2472Ile
NP_001341834.1:p.Thr2438Ile
NP_001341835.1:p.Thr2315Ile
LRG_130:g.155867C>T
NC_000005.9:g.112179084C>T
NM_000038.5:c.7793C>T

Protein change:

T2315I

Links:

dbSNP: rs747339588

NCBI 1000 Genomes Browser:

rs747339588

Molecular consequence:

NM_000038.6:c.7793C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.7793C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.7739C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.7793C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.7847C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.7823C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.7718C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.7709C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.7670C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.7616C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.7520C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.7490C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.7415C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.7313C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.6944C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial adenomatous polyposis 1 (FAP1)
Synonyms:: POLYPOSIS, ADENOMATOUS INTESTINAL; FAMILIAL ADENOMATOUS POLYPOSIS 1, ATTENUATED; APC-Associated Polyposis Conditions
Identifiers:: MONDO: MONDO:0021056; MedGen: C2713442; OMIM: 175100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001136950	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001495270	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 15, 2022)	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

SCV001136950

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Uncertain significance
(May 28, 2019)

unknown

clinical testing

Citation Link,

SCV001495270

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 15, 2022)

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Mendelics, SCV001136950.1

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

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001495270.4

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function. ClinVar contains an entry for this variant (Variation ID: 802147). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2598 of the APC protein (p.Thr2598Ile).

#	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: Nov 3, 2024

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