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NM_000038.6(APC):c.295C>T (p.Arg99Trp) AND Carcinoma of colon

Germline classification:
Likely 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:
RCV001353757.10

Allele description [Variation Report for NM_000038.6(APC):c.295C>T (p.Arg99Trp)]

NM_000038.6(APC):c.295C>T (p.Arg99Trp)

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.295C>T (p.Arg99Trp)
Other names:
p.R99W:CGG>TGG; NM_000038.6(APC):c.295C>T
HGVS:
  • NC_000005.10:g.112767263C>T
  • NG_008481.4:g.79743C>T
  • NM_000038.6:c.295C>TMANE SELECT
  • NM_001127510.3:c.295C>T
  • NM_001127511.3:c.325C>T
  • NM_001354895.2:c.295C>T
  • NM_001354896.2:c.295C>T
  • NM_001354897.2:c.325C>T
  • NM_001354898.2:c.220C>T
  • NM_001354899.2:c.295C>T
  • NM_001354900.2:c.118C>T
  • NM_001354901.2:c.118C>T
  • NM_001354902.2:c.325C>T
  • NM_001354903.2:c.295C>T
  • NM_001354904.2:c.220C>T
  • NM_001354905.2:c.118C>T
  • NM_001354906.2:c.-741C>T
  • NP_000029.2:p.Arg99Trp
  • NP_001120982.1:p.Arg99Trp
  • NP_001120983.2:p.Arg109Trp
  • NP_001341824.1:p.Arg99Trp
  • NP_001341825.1:p.Arg99Trp
  • NP_001341826.1:p.Arg109Trp
  • NP_001341827.1:p.Arg74Trp
  • NP_001341828.1:p.Arg99Trp
  • NP_001341829.1:p.Arg40Trp
  • NP_001341830.1:p.Arg40Trp
  • NP_001341831.1:p.Arg109Trp
  • NP_001341832.1:p.Arg99Trp
  • NP_001341833.1:p.Arg74Trp
  • NP_001341834.1:p.Arg40Trp
  • LRG_130t1:c.295C>T
  • LRG_130:g.79743C>T
  • NC_000005.9:g.112102960C>T
  • NM_000038.4:c.295C>T
  • NM_000038.5:c.295C>T
  • NM_001127510.2:c.295C>T
  • P25054:p.Arg99Trp
  • p.R99W
Protein change:
R109W
Links:
UniProtKB: P25054#VAR_009613; dbSNP: rs139196838
NCBI 1000 Genomes Browser:
rs139196838
Molecular consequence:
  • NM_001354906.2:c.-741C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000038.6:c.295C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127510.3:c.295C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127511.3:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354895.2:c.295C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354896.2:c.295C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354897.2:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354898.2:c.220C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354899.2:c.295C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354900.2:c.118C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354901.2:c.118C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354902.2:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354903.2:c.295C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354904.2:c.220C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354905.2:c.118C>T - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000591023Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Likely benignunknownclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000591023.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The APC p.Arg99Trp variant was identified in 7 of 3802 proband chromosomes (frequency: 0.002) from individuals or families with hamartomatous polyposis syndrome and familial adenomatous polyposis (Dobbie 1996, Heinimann 2001, Out 2015, Jelsig 2016, Kerr 2013). The variant was identified in dbSNP (rs139196838) as “with uncertain significance, other allele”, ClinVar (classified as uncertain significance by Counsyl, Mayo Clinic, Quest Diagnostics and 4 other submitters, likely benign by Color, Ambry Genetics, GeneDx and Sinai Health System and benign by Invitae and Integrated Genetics), LOVD 3.0 (observed 11x) and UMD-LSDB. The variant was identified in control databases in 113 of 282,846 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 95 of 129,170 chromosomes (freq: 0.0007), African in 9 of 24,968 chromosomes (freq: 0.0004), Other in 2 of 7224 chromosomes (freq: 0.0003), Finnish in 3 of 25,118 chromosomes (freq: 0.0001), Latino in 3 of 35,436 chromosomes (freq: 0.00009), East Asian in 1 of 19,944 chromosomes (freq: 0.00005), while the variant was not observed in the Ashkenazi Jewish and South Asian populations. The variant was identified in individuals in trans with pathogenic APC variants (p.Ser1222* and exon 15 deletion) (Kerr 2013). The p.Arg99 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 22, 2024