NM_000038.6(APC):c.449A>G (p.Lys150Arg) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jul 31, 2024
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:: RCV000211892.25

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]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000711457	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (May 22, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18199528, 28503720, 24033266
SCV000918433	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Mar 23, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18199528, 28503720, 21859464 Citation Link,
SCV002550563	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jul 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000711457

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(May 22, 2020)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000918433

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Mar 23, 2018)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV002550563

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Jul 31, 2024)

germline

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas.

Azzopardi D, Dallosso AR, Eliason K, Hendrickson BC, Jones N, Rawstorne E, Colley J, Moskvina V, Frye C, Sampson JR, Wenstrup R, Scholl T, Cheadle JP.

Cancer Res. 2008 Jan 15;68(2):358-63. doi: 10.1158/0008-5472.CAN-07-5733.

PubMed [citation]

PMID:: 18199528

See all PubMed Citations (5)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711457.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

proposed classification - variant undergoing re-assessment, contact laboratory

#	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		1	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918433.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: APC c.449A>G (p.Lys150Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 273686 control chromosomes. This frequency is not higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (2.2e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.449A>G has been reported in the literature in individuals affected with breast cancer and colon colorectal adenomas (Azzopardi_2008, Rummel_2017). These reports do not provide unequivocal conclusions about an association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002550563.7

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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