NM_000038.6(APC):c.5801C>T (p.Pro1934Leu) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Apr 24, 2021
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:: RCV000211923.23

Allele description [Variation Report for NM_000038.6(APC):c.5801C>T (p.Pro1934Leu)]

NM_000038.6(APC):c.5801C>T (p.Pro1934Leu)

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.5801C>T (p.Pro1934Leu)

Other names:

p.P1934L:CCC>CTC

HGVS:

NC_000005.10:g.112841395C>T
NG_008481.4:g.153875C>T
NM_000038.6:c.5801C>TMANE SELECT
NM_001127510.3:c.5801C>T
NM_001127511.3:c.5747C>T
NM_001354895.2:c.5801C>T
NM_001354896.2:c.5855C>T
NM_001354897.2:c.5831C>T
NM_001354898.2:c.5726C>T
NM_001354899.2:c.5717C>T
NM_001354900.2:c.5678C>T
NM_001354901.2:c.5624C>T
NM_001354902.2:c.5528C>T
NM_001354903.2:c.5498C>T
NM_001354904.2:c.5423C>T
NM_001354905.2:c.5321C>T
NM_001354906.2:c.4952C>T
NP_000029.2:p.Pro1934Leu
NP_001120982.1:p.Pro1934Leu
NP_001120983.2:p.Pro1916Leu
NP_001341824.1:p.Pro1934Leu
NP_001341825.1:p.Pro1952Leu
NP_001341826.1:p.Pro1944Leu
NP_001341827.1:p.Pro1909Leu
NP_001341828.1:p.Pro1906Leu
NP_001341829.1:p.Pro1893Leu
NP_001341830.1:p.Pro1875Leu
NP_001341831.1:p.Pro1843Leu
NP_001341832.1:p.Pro1833Leu
NP_001341833.1:p.Pro1808Leu
NP_001341834.1:p.Pro1774Leu
NP_001341835.1:p.Pro1651Leu
LRG_130t1:c.5801C>T
LRG_130:g.153875C>T
NC_000005.9:g.112177092C>T
NM_000038.4:c.5801C>T
NM_000038.5:c.5801C>T
p.P1934L

Protein change:

P1651L

Links:

dbSNP: rs587780600

NCBI 1000 Genomes Browser:

rs587780600

Molecular consequence:

NM_000038.6:c.5801C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.5801C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.5747C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.5801C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.5855C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.5831C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.5726C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.5717C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.5678C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.5624C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.5528C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.5498C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.5423C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.5321C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.4952C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000538300	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Mar 31, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000918453	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Apr 24, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21859464, 18199528, 26845104, 26580448, 29641532 Citation Link,
SCV002066674	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 12, 2020)	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

SCV000538300

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Mar 31, 2016)

germline

clinical testing

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

SCV000918453

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(Apr 24, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV002066674

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 12, 2020)

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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	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

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 (7)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000538300.1

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

Description

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 report in probands; ExAC: 6/11510 Latino; ClinVar: 3 VUS

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918453.2

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

Description

Variant summary: APC c.5801C>T (p.Pro1934Leu) results in a non-conservative amino acid change located in the 20-amino acid beta-catenin down-regulating repeats (20AAR) (Azzopardi_APC_Cancer Res_2008) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 249974 control chromosomes, predominantly at a frequency of 0.00041 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.5801C>T has been reported in the literature in individuals affected with multiple colorectal adenomas (Azzopardi 2008), and in other patients with various tumor phenotypes (Zhang 2015, Shirts 2015, Pritchard 2018). In one of these reports, this variant occurred in the germline of a patient with hypodiploid ALL and is unlikely to have been the primary causative lesion associated with the patient presentation (Zhang_2015). These report(s) do 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 (Azzopardi 2008). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=2; VUS, n=9). At-least two additional submitters have re-classified this variant as likely benign/benign since our previous evaluation. One submitter cites an unspecified co-occurrence with a mutation in another gene that clearly explains a proband's phenotype. Based on the evidence outlined above, the variant was classified as benign.

#	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 Genetic Services Laboratory, University of Chicago, SCV002066674.1

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

Description

This sequence change has been described in the gnomAD database with a global population frequency of 0.014% and 0.04% in the Latino sub population (dbSNP rs587780600). This sequence change has been reported in some patients with colorectal adenoma, one patient with adenomatous colorectal polyps and one patient with bilateral breast cancer (PMIDs: 21859464, 18199528 and 26845104). There is some experimental evidence that does not demonstrate damaging effect for this variant (PMID 18199528). The p.Pro1934Leu change affects a highly conserved amino acid residue located in the 20-amino acid repeat beta-catenin down-regulating domain as well as the SAMP repeats/axin binding domain (PMID 18199528). In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro1934Leu substitution. Due to these contrasting evidences, the clinical significance of the p.Pro1934Leu change remains unknown at this time.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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