NM_000038.6(APC):c.449A>G (p.Lys150Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Dec 11, 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:: RCV000130643.28

Allele description [Variation Report for NM_000038.6(APC):c.449A>G (p.Lys150Arg)]

NM_000038.6(APC):c.449A>G (p.Lys150Arg)

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.449A>G (p.Lys150Arg)

Other names:

p.K150R:AAA>AGA; CCDS4107.1:c.449A>G

HGVS:

NC_000005.10:g.112775655A>G
NG_008481.4:g.88135A>G
NM_000038.6:c.449A>GMANE SELECT
NM_001127510.3:c.449A>G
NM_001127511.3:c.479A>G
NM_001354895.2:c.449A>G
NM_001354896.2:c.449A>G
NM_001354897.2:c.479A>G
NM_001354898.2:c.374A>G
NM_001354899.2:c.449A>G
NM_001354900.2:c.272A>G
NM_001354901.2:c.272A>G
NM_001354902.2:c.479A>G
NM_001354903.2:c.449A>G
NM_001354904.2:c.374A>G
NM_001354905.2:c.272A>G
NM_001354906.2:c.-587A>G
NP_000029.2:p.Lys150Arg
NP_001120982.1:p.Lys150Arg
NP_001120983.2:p.Lys160Arg
NP_001341824.1:p.Lys150Arg
NP_001341825.1:p.Lys150Arg
NP_001341826.1:p.Lys160Arg
NP_001341827.1:p.Lys125Arg
NP_001341828.1:p.Lys150Arg
NP_001341829.1:p.Lys91Arg
NP_001341830.1:p.Lys91Arg
NP_001341831.1:p.Lys160Arg
NP_001341832.1:p.Lys150Arg
NP_001341833.1:p.Lys125Arg
NP_001341834.1:p.Lys91Arg
LRG_130t1:c.449A>G
LRG_130:g.88135A>G
NC_000005.9:g.112111352A>G
NM_000038.4:c.449A>G
NM_000038.5:c.449A>G
p.K150R

Protein change:

K125R

Links:

dbSNP: rs371085910

NCBI 1000 Genomes Browser:

rs371085910

Molecular consequence:

NM_001354906.2:c.-587A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000038.6:c.449A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.449A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.479A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.449A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.449A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.479A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.374A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.449A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.272A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.272A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.479A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.449A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.374A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.272A>G - missense variant - [Sequence Ontology: SO:0001583]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000185522	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Apr 10, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11257105, 16454848, 18199528, 25637381, 27535533, 28503720 Citation Link,
SCV000686977	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 11, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18199528, 21859464, 26580448, 28503720, 25741868
SCV000693483	True Health Diagnostics	no assertion criteria provided	Uncertain significance (Sep 25, 2017)	germline	clinical testing
SCV002534305	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Nov 1, 2021)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 18199528, 21859464, 26580448, 34301788, 28503720 Citation Link

Help

Summary from all submissions

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

Citations

PubMed

The ABC of APC.

Fearnhead NS, Britton MP, Bodmer WF.

Hum Mol Genet. 2001 Apr;10(7):721-33. Review.

PubMed [citation]

PMID:: 11257105

Familial adenomatous polyposis.

Galiatsatos P, Foulkes WD.

Am J Gastroenterol. 2006 Feb;101(2):385-98. Review.

PubMed [citation]

PMID:: 16454848

See all PubMed Citations (10)

Details of each submission

From Ambry Genetics, SCV000185522.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.

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

From Color Diagnostics, LLC DBA Color Health, SCV000686977.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces lysine with arginine at codon 150 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, protein functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer, colorectal adenomas, and rhabdosarcoma in the literature (PMID: 18199528, 21859464, 26580448, 28503720). This variant has been identified in 6/279048 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.

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

From True Health Diagnostics, SCV000693483.1

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

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

From Sema4, Sema4, SCV002534305.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (5)

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

Last Updated: May 1, 2024

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