NM_000038.6(APC):c.2476T>G (p.Leu826Val) AND not specified

Germline classification:: Benign/Likely benign (2 submissions)
Last evaluated:: Apr 29, 2021
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:: RCV000482678.15

Allele description [Variation Report for NM_000038.6(APC):c.2476T>G (p.Leu826Val)]

NM_000038.6(APC):c.2476T>G (p.Leu826Val)

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.2476T>G (p.Leu826Val)

Other names:

NM_000038.6(APC):c.2476T>G; p.Leu826Val

HGVS:

NC_000005.10:g.112838070T>G
NG_008481.4:g.150550T>G
NM_000038.6:c.2476T>GMANE SELECT
NM_001127510.3:c.2476T>G
NM_001127511.3:c.2422T>G
NM_001354895.2:c.2476T>G
NM_001354896.2:c.2530T>G
NM_001354897.2:c.2506T>G
NM_001354898.2:c.2401T>G
NM_001354899.2:c.2392T>G
NM_001354900.2:c.2353T>G
NM_001354901.2:c.2299T>G
NM_001354902.2:c.2203T>G
NM_001354903.2:c.2173T>G
NM_001354904.2:c.2098T>G
NM_001354905.2:c.1996T>G
NM_001354906.2:c.1627T>G
NP_000029.2:p.Leu826Val
NP_001120982.1:p.Leu826Val
NP_001120983.2:p.Leu808Val
NP_001341824.1:p.Leu826Val
NP_001341825.1:p.Leu844Val
NP_001341826.1:p.Leu836Val
NP_001341827.1:p.Leu801Val
NP_001341828.1:p.Leu798Val
NP_001341829.1:p.Leu785Val
NP_001341830.1:p.Leu767Val
NP_001341831.1:p.Leu735Val
NP_001341832.1:p.Leu725Val
NP_001341833.1:p.Leu700Val
NP_001341834.1:p.Leu666Val
NP_001341835.1:p.Leu543Val
LRG_130:g.150550T>G
NC_000005.9:g.112173767T>G
NM_000038.4:c.2476T>G
NM_000038.5:c.2476T>G
p.L826V

Protein change:

L543V

Links:

dbSNP: rs145245264

NCBI 1000 Genomes Browser:

rs145245264

Molecular consequence:

NM_000038.6:c.2476T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.2476T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.2422T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.2476T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.2530T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.2506T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.2401T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.2392T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.2353T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.2299T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.2203T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.2173T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.2098T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.1996T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.1627T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000916506	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Mar 1, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25186627, 26580448 Citation Link,
SCV002068615	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Apr 29, 2021)	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

SCV000916506

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Mar 1, 2021)

germline

clinical testing

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

Citation Link,

SCV002068615

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Benign
(Apr 29, 2021)

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	no	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

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

Germline Mutations in Predisposition Genes in Pediatric Cancer.

Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, et al.

N Engl J Med. 2015 Dec 10;373(24):2336-2346. doi: 10.1056/NEJMoa1508054. Epub 2015 Nov 18.

PubMed [citation]

PMID:: 26580448
PMCID:: PMC4734119

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000916506.2

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

Description

Variant summary: APC c.2476T>G (p.Leu826Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 250976 control chromosomes, predominantly at a frequency of 0.0014 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2476T>G has been reported in the literature in individuals affected with breast cancer and pediatric cancer (Tung_2014, Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely benign (n=3) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.

#	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 Genetic Services Laboratory, University of Chicago, SCV002068615.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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