NM_000038.6(APC):c.7316G>A (p.Arg2439His) AND Familial adenomatous polyposis 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 3, 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:: RCV003459377.3

Allele description [Variation Report for NM_000038.6(APC):c.7316G>A (p.Arg2439His)]

NM_000038.6(APC):c.7316G>A (p.Arg2439His)

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.7316G>A (p.Arg2439His)

HGVS:

NC_000005.10:g.112842910G>A
NG_008481.4:g.155390G>A
NM_000038.6:c.7316G>AMANE SELECT
NM_001127510.3:c.7316G>A
NM_001127511.3:c.7262G>A
NM_001354895.2:c.7316G>A
NM_001354896.2:c.7370G>A
NM_001354897.2:c.7346G>A
NM_001354898.2:c.7241G>A
NM_001354899.2:c.7232G>A
NM_001354900.2:c.7193G>A
NM_001354901.2:c.7139G>A
NM_001354902.2:c.7043G>A
NM_001354903.2:c.7013G>A
NM_001354904.2:c.6938G>A
NM_001354905.2:c.6836G>A
NM_001354906.2:c.6467G>A
NP_000029.2:p.Arg2439His
NP_001120982.1:p.Arg2439His
NP_001120983.2:p.Arg2421His
NP_001341824.1:p.Arg2439His
NP_001341825.1:p.Arg2457His
NP_001341826.1:p.Arg2449His
NP_001341827.1:p.Arg2414His
NP_001341828.1:p.Arg2411His
NP_001341829.1:p.Arg2398His
NP_001341830.1:p.Arg2380His
NP_001341831.1:p.Arg2348His
NP_001341832.1:p.Arg2338His
NP_001341833.1:p.Arg2313His
NP_001341834.1:p.Arg2279His
NP_001341835.1:p.Arg2156His
LRG_130:g.155390G>A
NC_000005.9:g.112178607G>A
NM_000038.5:c.7316G>A

Protein change:

R2156H

Links:

dbSNP: rs1221895599

NCBI 1000 Genomes Browser:

rs1221895599

Molecular consequence:

NM_000038.6:c.7316G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.7316G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.7262G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.7316G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.7370G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.7346G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.7241G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.7232G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.7193G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.7139G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.7043G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.7013G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.6938G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.6836G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.6467G>A - 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
SCV002127150	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 3, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004196411	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 16, 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

SCV002127150

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 3, 2023)

germline

clinical testing

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

SCV004196411

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 16, 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	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

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, SCV002127150.4

#	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 arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2439 of the APC protein (p.Arg2439His). This variant is not present in population databases (gnomAD no frequency). 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: 485161). 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 Baylor Genetics, SCV004196411.1

#	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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