NM_000038.5(APC):c.3927_3931delAAAGA (p.Glu1309Aspfs) AND Familial adenomatous polyposis 1

Clinical significance:Pathogenic (Last evaluated: Aug 27, 2017)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
8 submissions [Details]
Record status:
current
Accession:
RCV000000856.7

Allele description [Variation Report for NM_000038.5(APC):c.3927_3931delAAAGA (p.Glu1309Aspfs)]

NM_000038.5(APC):c.3927_3931delAAAGA (p.Glu1309Aspfs)

Gene:
APC:APC, WNT signaling pathway regulator [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
5q22.2
Genomic location:
Preferred name:
NM_000038.5(APC):c.3927_3931delAAAGA (p.Glu1309Aspfs)
HGVS:
  • NC_000005.10:g.112839521_112839525delAAAGA
  • NG_008481.4:g.152001_152005delAAAGA
  • NM_000038.5:c.3927_3931delAAAGA
  • NM_001127510.2:c.3927_3931delAAAGA
  • NM_001127511.2:c.3873_3877delAAAGA
  • NP_000029.2:p.Glu1309Aspfs
  • NP_001120982.1:p.Glu1309Aspfs
  • NP_001120983.2:p.Glu1291Aspfs
  • LRG_130:g.152001_152005delAAAGA
  • LRG_130p1:p.Glu1309Aspfs
  • LRG_130p2:p.Glu1309Aspfs
  • NC_000005.9:g.112175218_112175222delAAAGA
  • NM_000038.3:c.3927_3931delAAAGA
  • NM_000038.4:c.3927_3931delAAAGA
  • NM_000038.5:c.3927_3931del
  • NM_000038.5:c.3927_3931del5
  • c.3927_3931delAAAGA
  • p.E1309Dfs*4
  • p.Glu1309Aspfs*4
  • p.Glu1309AspfsX4
Links:
OMIM: 611731.0023; dbSNP: 121913224
NCBI 1000 Genomes Browser:
rs121913224
Molecular consequence:
  • NM_000038.5:c.3927_3931delAAAGA - frameshift variant - [Sequence Ontology: SO:0001589]
Observations:
2

Condition(s)

Name:
Familial adenomatous polyposis 1 (FAP1)
Synonyms:
Familial Adenomatous Polyposis; POLYPOSIS, ADENOMATOUS INTESTINAL; FAMILIAL ADENOMATOUS POLYPOSIS 1, ATTENUATED; See all synonyms [MedGen]
Identifiers:
MedGen: C2713442; OMIM: 175100

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000021006OMIMno assertion criteria providedPathogenic
(Jan 1, 1999)
unknownliterature only

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

SCV000040393GeneReviewsno assertion criteria providedpathologic
(Oct 27, 2011)
not providedcuration

SCV000058712Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicinecriteria provided, single submitter
Pathogenic
(Jan 9, 2012)
germlineclinical testing

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

SCV000189857Pathway Genomicsno assertion criteria providedPathogenic
(Jul 24, 2014)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000226389EGL Genetic Diagnostics,Eurofins Clinical Diagnosticscriteria provided, single submitter
Pathogenic
(Sep 14, 2015)
germlineclinical testing

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

Citation Link,

SCV000260059Invitaecriteria provided, single submitter
Pathogenic
(Jul 11, 2017)
germlineclinical testing

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

SCV000488559Counsylcriteria provided, single submitter
Pathogenic
(Apr 28, 2016)
unknownclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Counsyl Autosomal Dominant Disease Classification criteria (2015),

Citation Link,

SCV000616343GenePathDx,Causeway Health Care Private Ltdcriteria provided, single submitter
Pathogenic
(Aug 27, 2017)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided11not providednot providednot providedclinical testing
not providedgermlineunknown1not providednot providednot providednot providedclinical testing
not providednot providednot providednot providednot providednot providednot providednot providedliterature only
not providedunknownnot providednot providednot providednot providednot providednot providedliterature only
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
Indiangermlineyes11not providednot providednot providedclinical testing

Citations

PubMed

Regionally clustered APC mutations are associated with a severe phenotype and occur at a high frequency in new mutation cases of adenomatous polyposis coli.

Gayther SA, Wells D, SenGupta SB, Chapman P, Neale K, Tsioupra K, Delhanty JD.

Hum Mol Genet. 1994 Jan;3(1):53-6.

PubMed [citation]
PMID:
8162051

Identification of somatic APC gene mutations in periampullary adenomas in a patient with familial adenomatous polyposis (FAP).

Bapat B, Odze R, Mitri A, Berk T, Ward M, Gallinger S.

Hum Mol Genet. 1993 Nov;2(11):1957-9. No abstract available.

PubMed [citation]
PMID:
8281160
See all PubMed Citations (21)

Details of each submission

From OMIM, SCV000021006.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (4)

Description

In 9 patients with severe FAP1 (175100), Gayther et al. (1994) identified a 5-bp deletion at codon 1309 of the APC gene. The 5-bp deletion extends from the last base of codon 1309 to the first base of codon 1311; some refer to it as the 'codon 1309' APC mutation. This mutation may account for 9% of FAP due to mutations in the APC gene. The mutation tends to be associated with more severe and earlier onset disease and the presence of congenital hypertrophy of the retinal pigmented epithelium (CHRPE).

Bapat et al. (1993) identified a 5-bp deletion at codon 1309 in an FAP patient with periampullary adenomas. Two different somatic mutations in the APC gene (611731.0019; 611731.0020) were identified in 2 distinct adenomas from this patient.

Distante et al. (1996) described a 5-year-old girl with the mutation who presented with rectal bleeding from extensive polyposis of the colon; her father had had a colectomy for FAP at the age 23.

Shaoul et al. (1999) described a 6-year-old boy with FAP and congenital cholesteatoma (see 604183). They suggested that cholesteatoma represents a tumor-like lesion with biologic characteristics resembling other alimentary lesions of FAP. The patient first came to medical attention at the age of 4 years because of intermittent painless hematochezia. Colonoscopy at the age of 6 years showed multiple polyps of the colon. Eye examination showed hyperpigmented retinal lesions in the temporal retina of each eye, but radiographic studies of the mandible and maxilla showed no changes. The cholesteatoma was detected at the age of 4 years because of unilateral conductive hearing loss. Polyps had been detected in the patient's mother at the age of 25 years and a subtotal colectomy was performed. In both the mother and the child, DNA analysis identified a 5-bp deletion (GAAAG) at codons 1309-1311 in exon 15 of the APC gene. Shaoul et al. (1999) commented that mutations at codon 1309 have been associated with early development of adenomatous polyps and a greater risk of malignancies at an early age. Furthermore, the same mutations are strongly associated with the presence of congenital hypertrophy of the retinal pigment epithelium.

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

From GeneReviews, SCV000040393.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

Converted during submission to Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot providednot providednot providedAssert pathogenicitynot providednot providednot providednot provided

From Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine, SCV000058712.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (4)

Description

The Glu1309fs variant is the most frequent germline APC mutation and segregates with disease in more than 56 families (Friedl and Aretz 2005; GeneReviews). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1309 and leads to a premature stop codon 4 codons downstream which results in either a truncated or absent protein. This variant has also been shown to have occurred de novo as a spontaneous germline mutation with no parental bias (Ripa 2002; Aretz 2004). The presence of a heterozygous pathogenic mutation in APC is consistent with a diagnosis of Familial Adenomatous Polyposis (FAP) syndrome.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Pathway Genomics, SCV000189857.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From EGL Genetic Diagnostics,Eurofins Clinical Diagnostics, SCV000226389.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

From Invitae, SCV000260059.4

#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 Counsyl, SCV000488559.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From GenePathDx,Causeway Health Care Private Ltd, SCV000616343.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Indian1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not provided1not provided

Last Updated: Jan 18, 2018