NM_000038.6(APC):c.4732T>G (p.Cys1578Gly) AND not specified

Clinical significance:Uncertain significance (Last evaluated: Oct 21, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000507260.5

Allele description [Variation Report for NM_000038.6(APC):c.4732T>G (p.Cys1578Gly)]

NM_000038.6(APC):c.4732T>G (p.Cys1578Gly)

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.4732T>G (p.Cys1578Gly)
HGVS:
  • NC_000005.10:g.112840326T>G
  • NG_008481.4:g.152806T>G
  • NM_000038.6:c.4732T>GMANE SELECT
  • NM_001127510.3:c.4732T>G
  • NM_001127511.3:c.4678T>G
  • NM_001354895.2:c.4732T>G
  • NM_001354896.2:c.4786T>G
  • NM_001354897.2:c.4762T>G
  • NM_001354898.2:c.4657T>G
  • NM_001354899.2:c.4648T>G
  • NM_001354900.2:c.4609T>G
  • NM_001354901.2:c.4555T>G
  • NM_001354902.2:c.4459T>G
  • NM_001354903.2:c.4429T>G
  • NM_001354904.2:c.4354T>G
  • NM_001354905.2:c.4252T>G
  • NM_001354906.2:c.3883T>G
  • NP_000029.2:p.Cys1578Gly
  • NP_001120982.1:p.Cys1578Gly
  • NP_001120983.2:p.Cys1560Gly
  • NP_001341824.1:p.Cys1578Gly
  • NP_001341825.1:p.Cys1596Gly
  • NP_001341826.1:p.Cys1588Gly
  • NP_001341827.1:p.Cys1553Gly
  • NP_001341828.1:p.Cys1550Gly
  • NP_001341829.1:p.Cys1537Gly
  • NP_001341830.1:p.Cys1519Gly
  • NP_001341831.1:p.Cys1487Gly
  • NP_001341832.1:p.Cys1477Gly
  • NP_001341833.1:p.Cys1452Gly
  • NP_001341834.1:p.Cys1418Gly
  • NP_001341835.1:p.Cys1295Gly
  • LRG_130:g.152806T>G
  • NC_000005.9:g.112176023T>G
  • NM_000038.5:c.4732T>G
  • NM_001127510.2:c.4732T>G
  • p.C1578G
Protein change:
C1295G
Links:
dbSNP: rs138367627
NCBI 1000 Genomes Browser:
rs138367627
Molecular consequence:
  • NM_000038.6:c.4732T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127510.3:c.4732T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127511.3:c.4678T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354895.2:c.4732T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354896.2:c.4786T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354897.2:c.4762T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354898.2:c.4657T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354899.2:c.4648T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354900.2:c.4609T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354901.2:c.4555T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354902.2:c.4459T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354903.2:c.4429T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354904.2:c.4354T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354905.2:c.4252T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354906.2:c.3883T>G - 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
SCV000602503ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratoriescriteria provided, single submitter
Uncertain significance
(May 18, 2019)
germlineclinical testing

Citation Link,

SCV000918486Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Oct 21, 2019)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Actionable, pathogenic incidental findings in 1,000 participants' exomes.

Dorschner MO, Amendola LM, Turner EH, Robertson PD, Shirts BH, Gallego CJ, Bennett RL, Jones KL, Tokita MJ, Bennett JT, Kim JH, Rosenthal EA, Kim DS; National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project., Tabor HK, Bamshad MJ, Motulsky AG, Scott CR, Pritchard CC, Walsh T, Burke W, Raskind WH, et al.

Am J Hum Genet. 2013 Oct 3;93(4):631-40. doi: 10.1016/j.ajhg.2013.08.006. Epub 2013 Sep 19.

PubMed [citation]
PMID:
24055113
PMCID:
PMC3791261

Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer?

Minde DP, Anvarian Z, Rüdiger SG, Maurice MM.

Mol Cancer. 2011 Aug 22;10:101. doi: 10.1186/1476-4598-10-101. Review.

PubMed [citation]
PMID:
21859464
PMCID:
PMC3170638
See all PubMed Citations (4)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000602503.2

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

Description

The APC c.4732T>G; p.Cys1578Gly variant (rs138367627) is reported in the literature in an individual affected with multiple colorectal adenomas (Azzopardi 2008). This variant is found on a single chromosome (1/250924 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The cysteine at codon 1578 is highly conserved across species, located in the SAMP repeats/axin binding domain (Azzopardi 2008), and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, in functional assays, the p.Cys1578Gly variant suppressed beta-catenin-regulated transcription to the same extent as wildtype protein (Azzopardi 2008). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Azzopardi D et al. Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas. Cancer Res. 2008 Jan 15;68(2):358-63.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918486.2

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

Description

Variant summary: APC c.4732T>G (p.Cys1578Gly) results in a non-conservative amino acid change located in the SAMP repeats/axin binding domain (Azzopardi 2008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Five predict the variant creates a cryptic 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250924 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4732T>G has been reported in the literature in one individual affected with colorectal adenomas (Azzopard_2008). The report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Azzopard_2008). Four ClinVar submitter (evaluation after 2014) cite the variant as likely pathogenic (2x) and uncertain significance (2x). Based on the evidence outlined above, the variant was classified as uncertain significance.

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

Last Updated: Nov 27, 2021

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