NM_000038.6(APC):c.5302A>G (p.Lys1768Glu) AND not provided

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Jul 1, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000766438.19

Allele description [Variation Report for NM_000038.6(APC):c.5302A>G (p.Lys1768Glu)]

NM_000038.6(APC):c.5302A>G (p.Lys1768Glu)

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.5302A>G (p.Lys1768Glu)

Other names:

p.K1768E:AAG>GAG

HGVS:

NC_000005.10:g.112840896A>G
NG_008481.4:g.153376A>G
NM_000038.6:c.5302A>GMANE SELECT
NM_001127510.3:c.5302A>G
NM_001127511.3:c.5248A>G
NM_001354895.2:c.5302A>G
NM_001354896.2:c.5356A>G
NM_001354897.2:c.5332A>G
NM_001354898.2:c.5227A>G
NM_001354899.2:c.5218A>G
NM_001354900.2:c.5179A>G
NM_001354901.2:c.5125A>G
NM_001354902.2:c.5029A>G
NM_001354903.2:c.4999A>G
NM_001354904.2:c.4924A>G
NM_001354905.2:c.4822A>G
NM_001354906.2:c.4453A>G
NP_000029.2:p.Lys1768Glu
NP_001120982.1:p.Lys1768Glu
NP_001120983.2:p.Lys1750Glu
NP_001341824.1:p.Lys1768Glu
NP_001341825.1:p.Lys1786Glu
NP_001341826.1:p.Lys1778Glu
NP_001341827.1:p.Lys1743Glu
NP_001341828.1:p.Lys1740Glu
NP_001341829.1:p.Lys1727Glu
NP_001341830.1:p.Lys1709Glu
NP_001341831.1:p.Lys1677Glu
NP_001341832.1:p.Lys1667Glu
NP_001341833.1:p.Lys1642Glu
NP_001341834.1:p.Lys1608Glu
NP_001341835.1:p.Lys1485Glu
LRG_130:g.153376A>G
NC_000005.9:g.112176593A>G
NM_000038.5:c.5302A>G
p.K1768E

Protein change:

K1485E

Links:

dbSNP: rs199630012

NCBI 1000 Genomes Browser:

rs199630012

Molecular consequence:

NM_000038.6:c.5302A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.5302A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.5248A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.5302A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.5356A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.5332A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.5227A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.5218A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.5179A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.5125A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.5029A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.4999A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.4924A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.4822A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.4453A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149011	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Apr 11, 2017)	germline	clinical testing	Citation Link,
SCV000591190	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing
SCV001469313	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Sep 16, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004032617	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Jul 1, 2023)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Details of each submission

From GeneDx, SCV000149011.13

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is denoted APC c.5302A>G at the cDNA level, p.Lys1768Glu (K1768E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. APC Lys1768Glu was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Lys1768Glu occurs at a position that is not conserved and is located in the 20-amino acid repeat beta-catenin down-regulating domain and the SAMP repeats/axin binding domain (Azzopardi 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether APC Lys1768Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000591190.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The p.Lys1768Glu variant was not identified in the literature, nor was it identified in the HGMD, UMD, â€šÃ„ÃºInSiGHT Colon Cancer Databaseâ€šÃ„Ã¹, or the COSMIC database. The variant was listed in dbSNP (ID: rs199630012) and was identified in the NHLBI Exome Sequencing Project (Exome Variant Server) in 2 of 8598 European American alleles; though the low number and frequency of this variant is not substantive enough to determine the prevalence of this variant in the general population. The p.Lys1768 residue is conserved in most mammals, suggesting that this may be an important residue; however, the variant amino acid glutamic acid (Glu) is present in platypus, chicken, and zebrafish, increasing the likelihood that this variant may not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. One study suggests that this residue is part of one APC nuclear localization signal located from residues 1767-1772, and a substitution of alanine residues for lysine residues at positions 1768-1771 was shown to abolish nuclear localization signal activity (Zhang 2000). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001469313.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV004032617.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

APC: PM2, BP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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