NM_000038.6(APC):c.7495G>C (p.Val2499Leu) AND Classic or attenuated familial adenomatous polyposis

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 30, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003997871.2

Allele description [Variation Report for NM_000038.6(APC):c.7495G>C (p.Val2499Leu)]

NM_000038.6(APC):c.7495G>C (p.Val2499Leu)

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.7495G>C (p.Val2499Leu)

HGVS:

NC_000005.10:g.112843089G>C
NG_008481.4:g.155569G>C
NM_000038.6:c.7495G>CMANE SELECT
NM_001127510.3:c.7495G>C
NM_001127511.3:c.7441G>C
NM_001354895.2:c.7495G>C
NM_001354896.2:c.7549G>C
NM_001354897.2:c.7525G>C
NM_001354898.2:c.7420G>C
NM_001354899.2:c.7411G>C
NM_001354900.2:c.7372G>C
NM_001354901.2:c.7318G>C
NM_001354902.2:c.7222G>C
NM_001354903.2:c.7192G>C
NM_001354904.2:c.7117G>C
NM_001354905.2:c.7015G>C
NM_001354906.2:c.6646G>C
NP_000029.2:p.Val2499Leu
NP_001120982.1:p.Val2499Leu
NP_001120983.2:p.Val2481Leu
NP_001341824.1:p.Val2499Leu
NP_001341825.1:p.Val2517Leu
NP_001341826.1:p.Val2509Leu
NP_001341827.1:p.Val2474Leu
NP_001341828.1:p.Val2471Leu
NP_001341829.1:p.Val2458Leu
NP_001341830.1:p.Val2440Leu
NP_001341831.1:p.Val2408Leu
NP_001341832.1:p.Val2398Leu
NP_001341833.1:p.Val2373Leu
NP_001341834.1:p.Val2339Leu
NP_001341835.1:p.Val2216Leu
LRG_130:g.155569G>C
NC_000005.9:g.112178786G>C
NM_000038.5:c.7495G>C
P25054:p.Val2499Leu

Protein change:

V2216L

Links:

UniProtKB: P25054#VAR_053978; dbSNP: rs33941929

NCBI 1000 Genomes Browser:

rs33941929

Molecular consequence:

NM_000038.6:c.7495G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.7495G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.7441G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.7495G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.7549G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.7525G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.7420G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.7411G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.7372G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.7318G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.7222G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.7192G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.7117G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.7015G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.6646G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Classic or attenuated familial adenomatous polyposis
Identifiers:: MONDO: MONDO:0021057; MedGen: CN372698

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004835684	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Oct 30, 2023)	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

SCV004835684

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Oct 30, 2023)

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	2	not provided	not provided	108544	not provided	clinical testing

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

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004835684.1

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

Description

This missense variant replaces valine with leucine at codon 2499 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (DOI: 10.1101/2021.04.15.21255554). This variant has been identified in 1/246014 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	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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