NM_000038.6(APC):c.3404A>G (p.Tyr1135Cys) AND Familial adenomatous polyposis 1

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 28, 2025
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003767285.3

Allele description [Variation Report for NM_000038.6(APC):c.3404A>G (p.Tyr1135Cys)]

NM_000038.6(APC):c.3404A>G (p.Tyr1135Cys)

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.3404A>G (p.Tyr1135Cys)

HGVS:

NC_000005.10:g.112838998A>G
NG_008481.4:g.151478A>G
NM_000038.6:c.3404A>GMANE SELECT
NM_001127510.3:c.3404A>G
NM_001127511.3:c.3350A>G
NM_001354895.2:c.3404A>G
NM_001354896.2:c.3458A>G
NM_001354897.2:c.3434A>G
NM_001354898.2:c.3329A>G
NM_001354899.2:c.3320A>G
NM_001354900.2:c.3281A>G
NM_001354901.2:c.3227A>G
NM_001354902.2:c.3131A>G
NM_001354903.2:c.3101A>G
NM_001354904.2:c.3026A>G
NM_001354905.2:c.2924A>G
NM_001354906.2:c.2555A>G
NP_000029.2:p.Tyr1135Cys
NP_001120982.1:p.Tyr1135Cys
NP_001120983.2:p.Tyr1117Cys
NP_001341824.1:p.Tyr1135Cys
NP_001341825.1:p.Tyr1153Cys
NP_001341826.1:p.Tyr1145Cys
NP_001341827.1:p.Tyr1110Cys
NP_001341828.1:p.Tyr1107Cys
NP_001341829.1:p.Tyr1094Cys
NP_001341830.1:p.Tyr1076Cys
NP_001341831.1:p.Tyr1044Cys
NP_001341832.1:p.Tyr1034Cys
NP_001341833.1:p.Tyr1009Cys
NP_001341834.1:p.Tyr975Cys
NP_001341835.1:p.Tyr852Cys
LRG_130:g.151478A>G
NC_000005.9:g.112174695A>G
NM_000038.5:c.3404A>G

Protein change:

Y1009C

Links:

dbSNP: rs754916822

NCBI 1000 Genomes Browser:

rs754916822

Molecular consequence:

NM_000038.6:c.3404A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.3404A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.3350A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.3404A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.3458A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.3434A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.3329A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.3320A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.3281A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.3227A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.3131A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.3101A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.3026A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.2924A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.2555A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial adenomatous polyposis 1 (FAP1)
Synonyms:: POLYPOSIS, ADENOMATOUS INTESTINAL; FAMILIAL ADENOMATOUS POLYPOSIS 1, ATTENUATED; APC-Associated Polyposis Conditions
Identifiers:: MONDO: MONDO:0021056; MedGen: C2713442; OMIM: 175100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001570299	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 28, 2025)	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

SCV001570299

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 28, 2025)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001570299.5

#	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 replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1135 of the APC protein (p.Tyr1135Cys). This variant is present in population databases (rs754916822, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of familial adenomatous polyposis (internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 490262). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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 16, 2025

ClinVar

Relating variation to medicine