NM_000038.6(APC):c.1644G>C (p.Leu548Phe) AND Familial adenomatous polyposis 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 6, 2024
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:: RCV003770958.3

Allele description [Variation Report for NM_000038.6(APC):c.1644G>C (p.Leu548Phe)]

NM_000038.6(APC):c.1644G>C (p.Leu548Phe)

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.1644G>C (p.Leu548Phe)

HGVS:

NC_000005.10:g.112828873G>C
NG_008481.4:g.141353G>C
NM_000038.5:c.1644G>C
NM_000038.6:c.1644G>CMANE SELECT
NM_001127510.3:c.1644G>C
NM_001127511.3:c.1590G>C
NM_001354895.2:c.1644G>C
NM_001354896.2:c.1698G>C
NM_001354897.2:c.1674G>C
NM_001354898.2:c.1569G>C
NM_001354899.2:c.1560G>C
NM_001354900.2:c.1521G>C
NM_001354901.2:c.1467G>C
NM_001354902.2:c.1371G>C
NM_001354903.2:c.1341G>C
NM_001354904.2:c.1266G>C
NM_001354905.2:c.1164G>C
NM_001354906.2:c.795G>C
NP_000029.2:p.Leu548Phe
NP_001120982.1:p.Leu548Phe
NP_001120983.2:p.Leu530Phe
NP_001341824.1:p.Leu548Phe
NP_001341825.1:p.Leu566Phe
NP_001341826.1:p.Leu558Phe
NP_001341827.1:p.Leu523Phe
NP_001341828.1:p.Leu520Phe
NP_001341829.1:p.Leu507Phe
NP_001341830.1:p.Leu489Phe
NP_001341831.1:p.Leu457Phe
NP_001341832.1:p.Leu447Phe
NP_001341833.1:p.Leu422Phe
NP_001341834.1:p.Leu388Phe
NP_001341835.1:p.Leu265Phe
LRG_130:g.141353G>C
NC_000005.9:g.112164570G>C

Protein change:

L265F

Links:

dbSNP: rs1764009998

NCBI 1000 Genomes Browser:

rs1764009998

Molecular consequence:

NM_000038.6:c.1644G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.1644G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.1590G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.1644G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.1698G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.1674G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.1569G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.1560G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.1521G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.1467G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.1371G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.1341G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.1266G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.1164G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.795G>C - 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
SCV001539974	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 6, 2024)	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

SCV001539974

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 6, 2024)

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, SCV001539974.5

#	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 leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 548 of the APC protein (p.Leu548Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 1041944). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. 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.

#	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

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