NM_000038.6(APC):c.7099A>G (p.Thr2367Ala) AND Familial adenomatous polyposis 1

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Feb 1, 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:: RCV000692525.6

Allele description [Variation Report for NM_000038.6(APC):c.7099A>G (p.Thr2367Ala)]

NM_000038.6(APC):c.7099A>G (p.Thr2367Ala)

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.7099A>G (p.Thr2367Ala)

HGVS:

NC_000005.10:g.112842693A>G
NG_008481.4:g.155173A>G
NM_000038.6:c.7099A>GMANE SELECT
NM_001127510.3:c.7099A>G
NM_001127511.3:c.7045A>G
NM_001354895.2:c.7099A>G
NM_001354896.2:c.7153A>G
NM_001354897.2:c.7129A>G
NM_001354898.2:c.7024A>G
NM_001354899.2:c.7015A>G
NM_001354900.2:c.6976A>G
NM_001354901.2:c.6922A>G
NM_001354902.2:c.6826A>G
NM_001354903.2:c.6796A>G
NM_001354904.2:c.6721A>G
NM_001354905.2:c.6619A>G
NM_001354906.2:c.6250A>G
NP_000029.2:p.Thr2367Ala
NP_001120982.1:p.Thr2367Ala
NP_001120983.2:p.Thr2349Ala
NP_001341824.1:p.Thr2367Ala
NP_001341825.1:p.Thr2385Ala
NP_001341826.1:p.Thr2377Ala
NP_001341827.1:p.Thr2342Ala
NP_001341828.1:p.Thr2339Ala
NP_001341829.1:p.Thr2326Ala
NP_001341830.1:p.Thr2308Ala
NP_001341831.1:p.Thr2276Ala
NP_001341832.1:p.Thr2266Ala
NP_001341833.1:p.Thr2241Ala
NP_001341834.1:p.Thr2207Ala
NP_001341835.1:p.Thr2084Ala
LRG_130:g.155173A>G
NC_000005.9:g.112178390A>G
NM_000038.5:c.7099A>G

Protein change:

T2084A

Links:

dbSNP: rs772778630

NCBI 1000 Genomes Browser:

rs772778630

Molecular consequence:

NM_000038.6:c.7099A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.7099A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.7045A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.7099A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.7153A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.7129A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.7024A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.7015A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.6976A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.6922A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.6826A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.6796A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.6721A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.6619A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.6250A>G - 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
SCV000820352	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001136942	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV004203379	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 21, 2023)	unknown	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

SCV000820352

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 1, 2024)

germline

clinical testing

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

SCV001136942

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Uncertain significance
(May 28, 2019)

unknown

clinical testing

Citation Link,

SCV004203379

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 21, 2023)

unknown

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

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000820352.5

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

Description

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2367 of the APC protein (p.Thr2367Ala). This variant is present in population databases (rs772778630, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 571390). 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 with a negative predictive value of 95%. 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.

#	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 Mendelics, SCV001136942.1

#	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 Baylor Genetics, SCV004203379.1

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

#	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: Oct 26, 2024

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