NM_000038.6(APC):c.3386T>C (p.Leu1129Ser) AND Carcinoma of colon

Germline classification:: Benign (1 submission)
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

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:: RCV001353808.10

Allele description [Variation Report for NM_000038.6(APC):c.3386T>C (p.Leu1129Ser)]

NM_000038.6(APC):c.3386T>C (p.Leu1129Ser)

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.3386T>C (p.Leu1129Ser)

Other names:

p.L1129S:TTG>TCG; CCDS4107.1:c.3386T>C

HGVS:

NC_000005.10:g.112838980T>C
NG_008481.4:g.151460T>C
NM_000038.6:c.3386T>CMANE SELECT
NM_001127510.3:c.3386T>C
NM_001127511.3:c.3332T>C
NM_001354895.2:c.3386T>C
NM_001354896.2:c.3440T>C
NM_001354897.2:c.3416T>C
NM_001354898.2:c.3311T>C
NM_001354899.2:c.3302T>C
NM_001354900.2:c.3263T>C
NM_001354901.2:c.3209T>C
NM_001354902.2:c.3113T>C
NM_001354903.2:c.3083T>C
NM_001354904.2:c.3008T>C
NM_001354905.2:c.2906T>C
NM_001354906.2:c.2537T>C
NP_000029.2:p.Leu1129Ser
NP_000029.2:p.Leu1129Ser
NP_001120982.1:p.Leu1129Ser
NP_001120983.2:p.Leu1111Ser
NP_001341824.1:p.Leu1129Ser
NP_001341825.1:p.Leu1147Ser
NP_001341826.1:p.Leu1139Ser
NP_001341827.1:p.Leu1104Ser
NP_001341828.1:p.Leu1101Ser
NP_001341829.1:p.Leu1088Ser
NP_001341830.1:p.Leu1070Ser
NP_001341831.1:p.Leu1038Ser
NP_001341832.1:p.Leu1028Ser
NP_001341833.1:p.Leu1003Ser
NP_001341834.1:p.Leu969Ser
NP_001341835.1:p.Leu846Ser
LRG_130t1:c.3386T>C
LRG_130:g.151460T>C
LRG_130p1:p.Leu1129Ser
NC_000005.9:g.112174677T>C
NM_000038.4:c.3386T>C
NM_000038.5:c.3386T>C
NM_001127510.2:c.3386T>C
p.L1129S

Protein change:

L1003S

Links:

dbSNP: rs143638171

NCBI 1000 Genomes Browser:

rs143638171

Molecular consequence:

NM_000038.6:c.3386T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.3386T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.3332T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.3386T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.3440T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.3416T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.3311T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.3302T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.3263T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.3209T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.3113T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.3083T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.3008T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.2906T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.2537T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Carcinoma of colon (CRC)
Synonyms:: Colonic carcinoma; Colon carcinoma
Identifiers:: MONDO: MONDO:0002032; MedGen: C0699790

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F-box and associated interaction domains-containing protein [Arabidopsis thalian...
F-box and associated interaction domains-containing protein [Arabidopsis thaliana]
gi|15230161|ref|NP_189113.1|

Protein
Homo sapiens chromosome 12 WGS contig WGS_PUR_AC091534.7_41017 genomic sequence
Homo sapiens chromosome 12 WGS contig WGS_PUR_AC091534.7_41017 genomic sequence
gi|527463413|gb|KF455672.1|

Nucleotide
LOC100198376 [Hydra vulgaris]
LOC100198376 [Hydra vulgaris]
Gene ID:100198376

Gene
VWDE von Willebrand factor D and EGF domains [Pan troglodytes]
VWDE von Willebrand factor D and EGF domains [Pan troglodytes]
Gene ID:463267

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000591139	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	Benign	unknown	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000591139

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

See additional submitters

no assertion criteria provided

Benign

unknown

clinical testing

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

Details of each submission

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000591139.2

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

Description

The APC p.Leu1129Ser variant was identified in 8 of 5346 proband chromosomes (frequency: 0.001) from individuals or families with familial adenomatous polyposis, and was present at a similar (slightly higher) frequency in control chromosomes from healthy individuals (frequency: 0.003), suggesting that this variant may not have clinical significance. (Azzopardi 2008, Bodian 2014, Friedl 2005, Johnston 2012, Lefevre 2012, Plawski 2008, Scott2004, Zhou 2004). In addition, the variant was identified in several cohorts from the general population at subpolymorphic allelic frequencies, increasing the likelihood that this may be a low frequency benign variant (populations include: Exome Aggregation Consortium (ExAC) database (frequency: 0.0026 in Non-Finnish individuals), 1000 Genomes Project (frequency: 0.001), Exome Variant server Exome Sequencing Project (frequency: 0.0024)). The variant was also identified in dbSNP (ID: rs143638171), UMD (6X as a neutral variant), HGMD, COSMIC, InSiGHT Colon Cancer Gene Variant Database, the ClinVar database (classified as benign by Emory Genetics Laboratory, Biesecker Laboratory, and Ambry Genetics; classified as likely benign by GeneDX), and in the GeneInsight COGR database (classified as likely/suspected benign by two clinical laboratories). In addition, a co-occurring pathogenic variant in the APC gene was identified in this patient, also increasing the likelihood that the p.Leu1129Ser variant is benign. Conservation and in silico programs contradict the above information and suggest a possible impact to the protein; however this computational information is not predictive enough to assume pathogenicity. (The residue is conserved across mammals but not in all organisms including african clawed frog; four of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; one of five in silico splicing prediction programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts the creation of a potential 5â€šÃ„Ã´ splice site in the region of the variant, which is located outside of a known splicing consensus sequence). However, this variant was identified in one individual from our laboratory as co-occuring with a pathogenic APC variant, increasing the likelihood this variant is benign. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

#	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

Last Updated: Sep 16, 2024

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