NM_000038.6(APC):c.6354TGC[5] (p.Ala2122dup) AND Familial adenomatous polyposis 1

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Dec 7, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV001080265.4

Allele description [Variation Report for NM_000038.6(APC):c.6354TGC[5] (p.Ala2122dup)]

NM_000038.6(APC):c.6354TGC[5] (p.Ala2122dup)

Gene:
APC:APC regulator of WNT signaling pathway [Gene - OMIM - HGNC]
Variant type:
Microsatellite
Cytogenetic location:
5q22.2
Genomic location:
Preferred name:
NM_000038.6(APC):c.6354TGC[5] (p.Ala2122dup)
HGVS:
  • NC_000005.10:g.112841948TGC[5]
  • NG_008481.4:g.154428TGC[5]
  • NM_000038.6:c.6354TGC[5]MANE SELECT
  • NM_001127510.3:c.6354TGC[5]
  • NM_001127511.3:c.6300TGC[5]
  • NM_001354895.2:c.6354TGC[5]
  • NM_001354896.2:c.6408TGC[5]
  • NM_001354897.2:c.6384TGC[5]
  • NM_001354898.2:c.6279TGC[5]
  • NM_001354899.2:c.6270TGC[5]
  • NM_001354900.2:c.6231TGC[5]
  • NM_001354901.2:c.6177TGC[5]
  • NM_001354902.2:c.6081TGC[5]
  • NM_001354903.2:c.6051TGC[5]
  • NM_001354904.2:c.5976TGC[5]
  • NM_001354905.2:c.5874TGC[5]
  • NM_001354906.2:c.5505TGC[5]
  • NP_000029.2:p.Ala2122dup
  • NP_001120982.1:p.Ala2122dup
  • NP_001120983.2:p.Ala2104dup
  • NP_001341824.1:p.Ala2122dup
  • NP_001341825.1:p.Ala2140dup
  • NP_001341826.1:p.Ala2132dup
  • NP_001341827.1:p.Ala2097dup
  • NP_001341828.1:p.Ala2094dup
  • NP_001341829.1:p.Ala2081dup
  • NP_001341830.1:p.Ala2063dup
  • NP_001341831.1:p.Ala2031dup
  • NP_001341832.1:p.Ala2021dup
  • NP_001341833.1:p.Ala1996dup
  • NP_001341834.1:p.Ala1962dup
  • NP_001341835.1:p.Ala1839dup
  • LRG_130:g.154428TGC[5]
  • NC_000005.9:g.112177642_112177643insGCT
  • NC_000005.9:g.112177645TGC[5]
  • NM_000038.5:c.6363_6365dup
  • NM_000038.5:c.6363_6365dupTGC
  • p.Q2117_A2118INSC
Links:
dbSNP: rs587780602
NCBI 1000 Genomes Browser:
rs587780602
Molecular consequence:
  • NM_000038.6:c.6354TGC[5] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001127510.3:c.6354TGC[5] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001127511.3:c.6300TGC[5] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001354895.2:c.6354TGC[5] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001354896.2:c.6408TGC[5] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001354897.2:c.6384TGC[5] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001354898.2:c.6279TGC[5] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001354899.2:c.6270TGC[5] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001354900.2:c.6231TGC[5] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001354901.2:c.6177TGC[5] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001354902.2:c.6081TGC[5] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001354903.2:c.6051TGC[5] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001354904.2:c.5976TGC[5] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001354905.2:c.5874TGC[5] - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001354906.2:c.5505TGC[5] - inframe_insertion - [Sequence Ontology: SO:0001821]

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000166048Invitaecriteria provided, single submitter
Likely benign
(Dec 7, 2020)
germlineclinical testing

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

SCV000591198Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria providedUncertain significanceunknownclinical testing

SCV001482688Baylor Genetics - CSER-TexasKidsCanSeqcriteria provided, single submitter
Uncertain significance
(Apr 30, 2019)
paternalclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod

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):240-242.

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 Invitae, SCV000166048.12

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000591198.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The p.Ala2122dup variant was identified in 1 of 342 proband chromosomes (frequency: 0.003) from individuals or families with FAP, but was classified as a VUS by the authors (Out 2015). The variant was also identified in the Clinvitae database (1X with “uncertain significance”), COSMIC (1X found in a lung adenocarcinoma), ClinVar database (1X with uncertain significance, classified by Ambry Genetics), and UMD (1X with an “unclassified variant” classification). The variant was not identified in the general population cohort databases; 1000 Genomes Project, Exome Variant Server project or the Exome Aggregation Consortium (ExAC) database. This variant is an in-frame duplication resulting in the duplication of an Alanine (Ala) residue at codon 2122; the impact of this alteration on APC protein function is not known. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

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

From Baylor Genetics - CSER-TexasKidsCanSeq, SCV001482688.1

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

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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

Last Updated: Jun 23, 2021

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