NM_000038.6(APC):c.3084T>G (p.Ser1028Arg) AND Familial adenomatous polyposis 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 25, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV002554571.11

Allele description [Variation Report for NM_000038.6(APC):c.3084T>G (p.Ser1028Arg)]

NM_000038.6(APC):c.3084T>G (p.Ser1028Arg)

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.3084T>G (p.Ser1028Arg)

Other names:

NM_000038.6(APC):c.3084T>G; p.Ser1028Arg

HGVS:

NC_000005.10:g.112838678T>G
NG_008481.4:g.151158T>G
NM_000038.6:c.3084T>GMANE SELECT
NM_001127510.3:c.3084T>G
NM_001127511.3:c.3030T>G
NM_001354895.2:c.3084T>G
NM_001354896.2:c.3138T>G
NM_001354897.2:c.3114T>G
NM_001354898.2:c.3009T>G
NM_001354899.2:c.3000T>G
NM_001354900.2:c.2961T>G
NM_001354901.2:c.2907T>G
NM_001354902.2:c.2811T>G
NM_001354903.2:c.2781T>G
NM_001354904.2:c.2706T>G
NM_001354905.2:c.2604T>G
NM_001354906.2:c.2235T>G
NP_000029.2:p.Ser1028Arg
NP_001120982.1:p.Ser1028Arg
NP_001120983.2:p.Ser1010Arg
NP_001341824.1:p.Ser1028Arg
NP_001341825.1:p.Ser1046Arg
NP_001341826.1:p.Ser1038Arg
NP_001341827.1:p.Ser1003Arg
NP_001341828.1:p.Ser1000Arg
NP_001341829.1:p.Ser987Arg
NP_001341830.1:p.Ser969Arg
NP_001341831.1:p.Ser937Arg
NP_001341832.1:p.Ser927Arg
NP_001341833.1:p.Ser902Arg
NP_001341834.1:p.Ser868Arg
NP_001341835.1:p.Ser745Arg
LRG_130:g.151158T>G
NC_000005.9:g.112174375T>G
NM_000038.5:c.3084T>G

Protein change:

S1000R

Links:

dbSNP: rs876660265

NCBI 1000 Genomes Browser:

rs876660265

Molecular consequence:

NM_000038.6:c.3084T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.3084T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.3030T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.3084T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.3138T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.3114T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.3009T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.3000T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.2961T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.2907T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.2811T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.2781T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.2706T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.2604T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.2235T>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

Recent activity

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4-alpha-glucanotransferase [Komagataeibacter xylinus]
4-alpha-glucanotransferase [Komagataeibacter xylinus]
gi|1551367090|gnl|PRJNA421815|CXP35 0|gb|AZV37816.1|

Protein
vacuolar H+-ATPase SFD subunit, partial [Drosophila qiongzhouensis]
vacuolar H+-ATPase SFD subunit, partial [Drosophila qiongzhouensis]
gi|2079607669|gb|QYU72482.1|

Protein
Homo sapiens ribulose-5-phosphate-3-epimerase, mRNA (cDNA clone MGC:22637 IMAGE:...
Homo sapiens ribulose-5-phosphate-3-epimerase, mRNA (cDNA clone MGC:22637 IMAGE:4107315), complete cds
gi|16876981|gb|BC016764.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001234439	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 8, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003836594	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	reviewed by expert panel (ClinGen InSiGHT HCCP VCEP ACMG Specifications APC V1)	Uncertain significance (Feb 25, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001234439

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 8, 2019)

germline

clinical testing

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

SCV003836594

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

reviewed by expert panel

(ClinGen InSiGHT HCCP VCEP ACMG Specifications APC V1)

Uncertain significance
(Feb 25, 2023)

germline

curation

Citation Link

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, curation

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, SCV001234439.5

#	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 serine with arginine at codon 1028 of the APC protein (p.Ser1028Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with APC-related conditions. This variant is not present in population databases (ExAC no frequency).

#	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 ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel, SCV003836594.1

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

Description

The c.3084T>G variant in APC is a missense variant predicted to cause the substitution of serine by arginine at codon 1028 (p.Ser1028Arg). Another missense variant c.3084T>A (p.Ser1028Arg) at the same nucleotide position leading to the same amino acid change has been classified as Likely Pathogenic for FAP according to the APC VCEP specifications (PS1_Moderate). Another missense variant c.3083G>T (p.Ser1028Ile) in the same codon leading to a different amino acid change has been classified as Likely Pathogenic for FAP according to the APC VCEP specifications (PM5_Supporting). This variant was identified in 1 proband with polyposis not meeting phenotype criteria (PS4_variable not met; Invitae internal data). Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In Summary, due to insufficient evidence, this variant is a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS1_Moderate, PM2_Supporting, PM5_Supporting (VCEP specifications version 1; date of approval: 12/12/2022).

#	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 13, 2024

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