NM_000038.6(APC):c.1242C>T (p.Arg414=) AND Familial adenomatous polyposis 1

Germline classification:: Benign (3 submissions)
Last evaluated:: Feb 18, 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:: RCV003148671.10

Allele description [Variation Report for NM_000038.6(APC):c.1242C>T (p.Arg414=)]

NM_000038.6(APC):c.1242C>T (p.Arg414=)

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.1242C>T (p.Arg414=)

Other names:

NM_000038.6(APC):c.1242C>T; p.Arg414=

HGVS:

NC_000005.10:g.112819274C>T
NG_008481.4:g.131754C>T
NM_000038.6:c.1242C>TMANE SELECT
NM_001127510.3:c.1242C>T
NM_001127511.3:c.1188C>T
NM_001354895.2:c.1242C>T
NM_001354896.2:c.1242C>T
NM_001354897.2:c.1272C>T
NM_001354898.2:c.1167C>T
NM_001354899.2:c.1158C>T
NM_001354900.2:c.1065C>T
NM_001354901.2:c.1065C>T
NM_001354902.2:c.969C>T
NM_001354903.2:c.939C>T
NM_001354904.2:c.864C>T
NM_001354905.2:c.762C>T
NM_001354906.2:c.393C>T
NP_000029.2:p.Arg414=
NP_001120982.1:p.Arg414=
NP_001120983.2:p.Arg396=
NP_001341824.1:p.Arg414=
NP_001341825.1:p.Arg414=
NP_001341826.1:p.Arg424=
NP_001341827.1:p.Arg389=
NP_001341828.1:p.Arg386=
NP_001341829.1:p.Arg355=
NP_001341830.1:p.Arg355=
NP_001341831.1:p.Arg323=
NP_001341832.1:p.Arg313=
NP_001341833.1:p.Arg288=
NP_001341834.1:p.Arg254=
NP_001341835.1:p.Arg131=
LRG_130t1:c.1242C>T
LRG_130:g.131754C>T
NC_000005.9:g.112154971C>T
NM_000038.4:c.1242C>T
NM_000038.5:c.1242C>T
p.Arg414Arg

Links:

dbSNP: rs751423790

NCBI 1000 Genomes Browser:

rs751423790

Molecular consequence:

NM_000038.6:c.1242C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001127510.3:c.1242C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001127511.3:c.1188C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354895.2:c.1242C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354896.2:c.1242C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354897.2:c.1272C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354898.2:c.1167C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354899.2:c.1158C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354900.2:c.1065C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354901.2:c.1065C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354902.2:c.969C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354903.2:c.939C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354904.2:c.864C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354905.2:c.762C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354906.2:c.393C>T - synonymous variant - [Sequence Ontology: SO:0001819]

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
SCV000252906	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Dec 18, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003836580	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	reviewed by expert panel (ClinGen InSiGHT HCCP VCEP ACMG Specifications APC V1)	Benign (Feb 18, 2023)	germline	curation	Citation Link,
SCV004931804	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Benign (Mar 1, 2024)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000252906

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Dec 18, 2023)

germline

clinical testing

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

SCV003836580

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

reviewed by expert panel

(ClinGen InSiGHT HCCP VCEP ACMG Specifications APC V1)

Benign
(Feb 18, 2023)

germline

curation

Citation Link,

SCV004931804

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Benign
(Mar 1, 2024)

unknown

clinical testing

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
not provided	unknown	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 Invitae, SCV000252906.10

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

#	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, SCV003836580.1

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

Description

The c.1242C>T (p.Arg414=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). This variant has been observed in heterozygous state in 11 healthy unrelated adult individuals worth 11 (more than 10) healthy individual points in total (BS2; Ambry internal data). While RT-PCR from internal data demonstrated no impact of the variant on splicing (Ambry Internal Data), transcription assays (not otherwise specified) in the literature demonstrated that the variant impacts splicing by leading to partial exon 10 skipping (p.V313_Q412del) (PMID 20685668). Functional evidence was disregarded in the classification of this variant as they showed conflicting results. The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.000034 (4/117512 alleles) in European (non-Finnish) population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (0.00001) for BS1. In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS1, BS2, BP4, and BP7 (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

From Myriad Genetics, Inc., SCV004931804.1

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

Description

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Aug 18, 2024

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