NM_000038.6(APC):c.7717A>G (p.Ile2573Val) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jul 31, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000236063.24

Allele description [Variation Report for NM_000038.6(APC):c.7717A>G (p.Ile2573Val)]

NM_000038.6(APC):c.7717A>G (p.Ile2573Val)

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.7717A>G (p.Ile2573Val)

HGVS:

NC_000005.10:g.112843311A>G
NG_008481.4:g.155791A>G
NM_000038.6:c.7717A>GMANE SELECT
NM_001127510.3:c.7717A>G
NM_001127511.3:c.7663A>G
NM_001354895.2:c.7717A>G
NM_001354896.2:c.7771A>G
NM_001354897.2:c.7747A>G
NM_001354898.2:c.7642A>G
NM_001354899.2:c.7633A>G
NM_001354900.2:c.7594A>G
NM_001354901.2:c.7540A>G
NM_001354902.2:c.7444A>G
NM_001354903.2:c.7414A>G
NM_001354904.2:c.7339A>G
NM_001354905.2:c.7237A>G
NM_001354906.2:c.6868A>G
NP_000029.2:p.Ile2573Val
NP_001120982.1:p.Ile2573Val
NP_001120983.2:p.Ile2555Val
NP_001341824.1:p.Ile2573Val
NP_001341825.1:p.Ile2591Val
NP_001341826.1:p.Ile2583Val
NP_001341827.1:p.Ile2548Val
NP_001341828.1:p.Ile2545Val
NP_001341829.1:p.Ile2532Val
NP_001341830.1:p.Ile2514Val
NP_001341831.1:p.Ile2482Val
NP_001341832.1:p.Ile2472Val
NP_001341833.1:p.Ile2447Val
NP_001341834.1:p.Ile2413Val
NP_001341835.1:p.Ile2290Val
LRG_130t1:c.7717A>G
LRG_130:g.155791A>G
NC_000005.9:g.112179008A>G
NM_000038.4:c.7717A>G
NM_000038.5:c.7717A>G
p.I2573V

Protein change:

I2290V

Links:

dbSNP: rs145444830

NCBI 1000 Genomes Browser:

rs145444830

Molecular consequence:

NM_000038.6:c.7717A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.7717A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.7663A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.7717A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.7771A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.7747A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.7642A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.7633A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.7594A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.7540A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.7444A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.7414A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.7339A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.7237A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.6868A>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
SCV000538305	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jan 24, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002550663	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jul 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004099683	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Sep 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000538305

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jan 24, 2017)

germline

clinical testing

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

SCV002550663

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Jul 31, 2024)

germline

clinical testing

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

SCV004099683

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Sep 11, 2023)

germline

clinical testing

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

Citation Link

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

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

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

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000538305.1

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

Description

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 2 individuals with colorectal adenomas and 1 individual with no cancer. The variant has a Max MAF of 0.03% in ExAC (18 alleles) and 0.02% in gnomAD (21 alleles). Frequency too high for disease? It is classified with 2 stars in ClinVar as VUS by Invitae, Ambry, GeneDx, CSER_CC_NCGL, and Biesecker lab. 10 non-mammals have a Val at this position.

#	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 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002550663.7

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004099683.1

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

Description

Variant summary: APC c.7717A>G (p.Ile2573Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 250818 control chromosomes, predominantly at a frequency of 0.00018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.5 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 Non-Finnish European origin. c.7717A>G has been reported in the literature in and individual affected with Colorectal Adenomas (Azzopard_2008) without evidence for causality. This report does 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. The following publication have been ascertained in the context of this evaluation (PMID: 18199528). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=6) and VUS (n=6). 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

Last Updated: Sep 16, 2024

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