NM_000038.6(APC):c.3650A>C (p.Asn1217Thr) AND not specified

Clinical significance:Likely benign (Last evaluated: Sep 28, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000120014.5

Allele description [Variation Report for NM_000038.6(APC):c.3650A>C (p.Asn1217Thr)]

NM_000038.6(APC):c.3650A>C (p.Asn1217Thr)

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.3650A>C (p.Asn1217Thr)
HGVS:
  • NC_000005.10:g.112839244A>C
  • NG_008481.4:g.151724A>C
  • NM_000038.6:c.3650A>CMANE SELECT
  • NM_001127510.3:c.3650A>C
  • NM_001127511.3:c.3596A>C
  • NM_001354895.2:c.3650A>C
  • NM_001354896.2:c.3704A>C
  • NM_001354897.2:c.3680A>C
  • NM_001354898.2:c.3575A>C
  • NM_001354899.2:c.3566A>C
  • NM_001354900.2:c.3527A>C
  • NM_001354901.2:c.3473A>C
  • NM_001354902.2:c.3377A>C
  • NM_001354903.2:c.3347A>C
  • NM_001354904.2:c.3272A>C
  • NM_001354905.2:c.3170A>C
  • NM_001354906.2:c.2801A>C
  • NP_000029.2:p.Asn1217Thr
  • NP_001120982.1:p.Asn1217Thr
  • NP_001120983.2:p.Asn1199Thr
  • NP_001341824.1:p.Asn1217Thr
  • NP_001341825.1:p.Asn1235Thr
  • NP_001341826.1:p.Asn1227Thr
  • NP_001341827.1:p.Asn1192Thr
  • NP_001341828.1:p.Asn1189Thr
  • NP_001341829.1:p.Asn1176Thr
  • NP_001341830.1:p.Asn1158Thr
  • NP_001341831.1:p.Asn1126Thr
  • NP_001341832.1:p.Asn1116Thr
  • NP_001341833.1:p.Asn1091Thr
  • NP_001341834.1:p.Asn1057Thr
  • NP_001341835.1:p.Asn934Thr
  • LRG_130:g.151724A>C
  • NC_000005.9:g.112174941A>C
  • NM_000038.5:c.3650A>C
  • p.N1217T
Protein change:
N1057T
Links:
dbSNP: rs138933660
NCBI 1000 Genomes Browser:
rs138933660
Molecular consequence:
  • NM_000038.6:c.3650A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127510.3:c.3650A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127511.3:c.3596A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354895.2:c.3650A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354896.2:c.3704A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354897.2:c.3680A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354898.2:c.3575A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354899.2:c.3566A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354900.2:c.3527A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354901.2:c.3473A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354902.2:c.3377A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354903.2:c.3347A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354904.2:c.3272A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354905.2:c.3170A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354906.2:c.2801A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000084144ITMIno assertion providednot providedgermlinereference population

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

SCV000694035Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely benign
(Sep 28, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Description

Please see associated publication for description of ethnicities

SCV000084144

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
Africangermlineunknownnot providednot providednot provided43not providedreference population
African_Europeangermlineunknownnot providednot providednot provided46not providedreference population
Central_Asiangermlineunknownnot providednot providednot provided50not providedreference population
East_Asiangermlineunknownnot providednot providednot provided62not providedreference population
Europeangermlineunknownnot providednot providednot provided331not providedreference population
Hispanicgermlineunknownnot providednot providednot provided118not providedreference population
Whole_cohortgermlineunknownnot providednot providednot provided681not providedreference population

Citations

PubMed

Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.

Bodian DL, McCutcheon JN, Kothiyal P, Huddleston KC, Iyer RK, Vockley JG, Niederhuber JE.

PLoS One. 2014;9(4):e94554. doi: 10.1371/journal.pone.0094554.

PubMed [citation]
PMID:
24728327
PMCID:
PMC3984285

Dominant-negative ALK2 allele associates with congenital heart defects.

Smith KA, Joziasse IC, Chocron S, van Dinther M, Guryev V, Verhoeven MC, Rehmann H, van der Smagt JJ, Doevendans PA, Cuppen E, Mulder BJ, Ten Dijke P, Bakkers J.

Circulation. 2009 Jun 23;119(24):3062-9. doi: 10.1161/CIRCULATIONAHA.108.843714. Epub 2009 Jun 8.

PubMed [citation]
PMID:
19506109
See all PubMed Citations (4)

Details of each submission

From ITMI, SCV000084144.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Africannot providednot providednot providedreference population PubMed (1)
2African_Europeannot providednot providednot providedreference population PubMed (1)
3Central_Asiannot providednot providednot providedreference population PubMed (1)
4East_Asiannot providednot providednot providedreference population PubMed (1)
5Europeannot providednot providednot providedreference population PubMed (1)
6Hispanicnot providednot providednot providedreference population PubMed (1)
7Whole_cohortnot providednot providednot providedreference population PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown43not provideddiscoverynot provided0.0116not providednot provided
2germlineunknown46not provideddiscoverynot provided0.0109not providednot provided
3germlineunknown50not provideddiscoverynot provided0not providednot provided
4germlineunknown62not provideddiscoverynot provided0not providednot provided
5germlineunknown331not provideddiscoverynot provided0not providednot provided
6germlineunknown118not provideddiscoverynot provided0not providednot provided
7germlineunknown681not provideddiscoverynot provided0.0015not providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694035.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: APC c.3650A>C (p.Asn1217Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251760 control chromosomes, predominantly at a frequency of 0.0026 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 36 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. The variant, c.3650A>C has been reported in the literature in an individual affected with cancer of cecum and also in breast cancer high-risk families. (Pearlman_2016, Bonache_2018) . However, 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. Six other ClinVar submitters (evaluation after 2014) cite the variant as likely bening/benign (n=4) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 4, 2021

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