NM_000038.6(APC):c.705A>G (p.Leu235=) AND Familial adenomatous polyposis 1

Germline classification:: Benign (4 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:: RCV002514368.11

Allele description [Variation Report for NM_000038.6(APC):c.705A>G (p.Leu235=)]

NM_000038.6(APC):c.705A>G (p.Leu235=)

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.705A>G (p.Leu235=)

Other names:

p.L235L:TTA>TTG; CCDS4107.1:c.705A>G; NM_000038.6(APC):c.705A>G; p.Leu235=

HGVS:

NC_000005.10:g.112792505A>G
NG_008481.4:g.104985A>G
NM_000038.6:c.705A>GMANE SELECT
NM_001127510.3:c.705A>G
NM_001127511.3:c.676-8774A>G
NM_001354895.2:c.705A>G
NM_001354896.2:c.705A>G
NM_001354897.2:c.735A>G
NM_001354898.2:c.630A>G
NM_001354899.2:c.646-8774A>G
NM_001354900.2:c.528A>G
NM_001354901.2:c.528A>G
NM_001354902.2:c.735A>G
NM_001354903.2:c.705A>G
NM_001354904.2:c.630A>G
NM_001354905.2:c.528A>G
NM_001354906.2:c.-331A>G
NP_000029.2:p.Leu235=
NP_001120982.1:p.Leu235=
NP_001341824.1:p.Leu235=
NP_001341825.1:p.Leu235=
NP_001341826.1:p.Leu245=
NP_001341827.1:p.Leu210=
NP_001341829.1:p.Leu176=
NP_001341830.1:p.Leu176=
NP_001341831.1:p.Leu245=
NP_001341832.1:p.Leu235=
NP_001341833.1:p.Leu210=
NP_001341834.1:p.Leu176=
LRG_130t1:c.705A>G
LRG_130:g.104985A>G
NC_000005.9:g.112128202A>G
NM_000038.4:c.705A>G
NM_000038.5:c.705A>G
NM_001127510.2:c.705A>G
NP_000029.2:p.(=)
p.L235L
p.Leu235Leu

Links:

dbSNP: rs147036141

NCBI 1000 Genomes Browser:

rs147036141

Molecular consequence:

NM_001354906.2:c.-331A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001127511.3:c.676-8774A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354899.2:c.646-8774A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000038.6:c.705A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001127510.3:c.705A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354895.2:c.705A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354896.2:c.705A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354897.2:c.735A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354898.2:c.630A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354900.2:c.528A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354901.2:c.528A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354902.2:c.735A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354903.2:c.705A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354904.2:c.630A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354905.2:c.528A>G - 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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Homo sapiens DARS1 antisense RNA 1 (DARS1-AS1), transcript variant 2, long non-c...
Homo sapiens DARS1 antisense RNA 1 (DARS1-AS1), transcript variant 2, long non-coding RNA
gi|571330855|ref|NR_110200.1|

Nucleotide
Taxonomy Links for Gene (Select 810608) (1)
Taxonomy
PMC Links for Gene (Select 810608) (1)
PMC
Acetobacteraceae bacterium CS8 16S ribosomal RNA gene, partial sequence
Acetobacteraceae bacterium CS8 16S ribosomal RNA gene, partial sequence
gi|509046593|gb|JX896637.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000252593	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Feb 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003836570	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,
SCV004015859	KCCC/NGS Laboratory, Kuwait Cancer Control Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Jul 7, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004931021	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Benign (Feb 26, 2024)	unknown	clinical testing	Citation Link

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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	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000252593.12

#	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, SCV003836570.1

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

Description

The c.705A>G (p.Leu235=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing by multiple splicing predictors including SpliceAI, VarSEAK and MaxEntScan (BP4, BP7). This variant has been observed 3 times in homozygous state in gnomAD 2.1.1 (BS2). The highest population minor allele frequency in the non-cancer population of gnomAD v2.1.1 is 0.004669 in the Finnish population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (>0.001) for BA1, and therefore meets this criterion (BA1). 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: BA1, BS2, BP4, and BP7 (Specification Version 1.0; 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 KCCC/NGS Laboratory, Kuwait Cancer Control Center, SCV004015859.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004931021.1

#	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: Nov 10, 2024

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