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NM_000038.6(APC):c.5216A>G (p.Lys1739Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:
Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:
Mar 30, 2023
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:
RCV000163875.21

Allele description [Variation Report for NM_000038.6(APC):c.5216A>G (p.Lys1739Arg)]

NM_000038.6(APC):c.5216A>G (p.Lys1739Arg)

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.5216A>G (p.Lys1739Arg)
HGVS:
  • NC_000005.10:g.112840810A>G
  • NG_008481.4:g.153290A>G
  • NM_000038.6:c.5216A>GMANE SELECT
  • NM_001127510.3:c.5216A>G
  • NM_001127511.3:c.5162A>G
  • NM_001354895.2:c.5216A>G
  • NM_001354896.2:c.5270A>G
  • NM_001354897.2:c.5246A>G
  • NM_001354898.2:c.5141A>G
  • NM_001354899.2:c.5132A>G
  • NM_001354900.2:c.5093A>G
  • NM_001354901.2:c.5039A>G
  • NM_001354902.2:c.4943A>G
  • NM_001354903.2:c.4913A>G
  • NM_001354904.2:c.4838A>G
  • NM_001354905.2:c.4736A>G
  • NM_001354906.2:c.4367A>G
  • NP_000029.2:p.Lys1739Arg
  • NP_001120982.1:p.Lys1739Arg
  • NP_001120983.2:p.Lys1721Arg
  • NP_001341824.1:p.Lys1739Arg
  • NP_001341825.1:p.Lys1757Arg
  • NP_001341826.1:p.Lys1749Arg
  • NP_001341827.1:p.Lys1714Arg
  • NP_001341828.1:p.Lys1711Arg
  • NP_001341829.1:p.Lys1698Arg
  • NP_001341830.1:p.Lys1680Arg
  • NP_001341831.1:p.Lys1648Arg
  • NP_001341832.1:p.Lys1638Arg
  • NP_001341833.1:p.Lys1613Arg
  • NP_001341834.1:p.Lys1579Arg
  • NP_001341835.1:p.Lys1456Arg
  • LRG_130t1:c.5216A>G
  • LRG_130:g.153290A>G
  • NC_000005.9:g.112176507A>G
  • NM_000038.4:c.5216A>G
  • NM_000038.5:c.5216A>G
  • p.K1739R
Protein change:
K1456R
Links:
dbSNP: rs769558291
NCBI 1000 Genomes Browser:
rs769558291
Molecular consequence:
  • NM_000038.6:c.5216A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127510.3:c.5216A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127511.3:c.5162A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354895.2:c.5216A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354896.2:c.5270A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354897.2:c.5246A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354898.2:c.5141A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354899.2:c.5132A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354900.2:c.5093A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354901.2:c.5039A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354902.2:c.4943A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354903.2:c.4913A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354904.2:c.4838A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354905.2:c.4736A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354906.2:c.4367A>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000214462Ambry Genetics
criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)		Likely benign
(Aug 11, 2020) 		germlineclinical testing

Citation Link,

SCV000681715Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Mar 30, 2023) 		germlineclinical testing

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

SCV002535087Sema4, Sema4
criteria provided, single submitter

(Sema4 Curation Guidelines)		Uncertain significance
(Aug 18, 2021) 		germlinecuration

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing, curation

Citations

PubMed

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 Ambry Genetics, SCV000214462.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Diagnostics, LLC DBA Color Health, SCV000681715.5

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

Description

This missense variant replaces lysine with arginine at codon 1739 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 4/282064 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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

From Sema4, Sema4, SCV002535087.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 15, 2024