NM_000038.6(APC):c.7786T>G (p.Ser2596Ala) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Nov 30, 2018
Review status:: criteria provided, conflicting classifications

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:: RCV000478677.20

Allele description [Variation Report for NM_000038.6(APC):c.7786T>G (p.Ser2596Ala)]

NM_000038.6(APC):c.7786T>G (p.Ser2596Ala)

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.7786T>G (p.Ser2596Ala)

HGVS:

NC_000005.10:g.112843380T>G
NG_008481.4:g.155860T>G
NM_000038.6:c.7786T>GMANE SELECT
NM_001127510.3:c.7786T>G
NM_001127511.3:c.7732T>G
NM_001354895.2:c.7786T>G
NM_001354896.2:c.7840T>G
NM_001354897.2:c.7816T>G
NM_001354898.2:c.7711T>G
NM_001354899.2:c.7702T>G
NM_001354900.2:c.7663T>G
NM_001354901.2:c.7609T>G
NM_001354902.2:c.7513T>G
NM_001354903.2:c.7483T>G
NM_001354904.2:c.7408T>G
NM_001354905.2:c.7306T>G
NM_001354906.2:c.6937T>G
NP_000029.2:p.Ser2596Ala
NP_001120982.1:p.Ser2596Ala
NP_001120983.2:p.Ser2578Ala
NP_001341824.1:p.Ser2596Ala
NP_001341825.1:p.Ser2614Ala
NP_001341826.1:p.Ser2606Ala
NP_001341827.1:p.Ser2571Ala
NP_001341828.1:p.Ser2568Ala
NP_001341829.1:p.Ser2555Ala
NP_001341830.1:p.Ser2537Ala
NP_001341831.1:p.Ser2505Ala
NP_001341832.1:p.Ser2495Ala
NP_001341833.1:p.Ser2470Ala
NP_001341834.1:p.Ser2436Ala
NP_001341835.1:p.Ser2313Ala
LRG_130t1:c.7786T>G
LRG_130:g.155860T>G
NC_000005.9:g.112179077T>G
NM_000038.4:c.7786T>G
NM_000038.5:c.7786T>G
NM_001127510.2:c.7786T>G
p.S2596A

Protein change:

S2313A

Links:

dbSNP: rs138137162

NCBI 1000 Genomes Browser:

rs138137162

Molecular consequence:

NM_000038.6:c.7786T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.7786T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.7732T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.7786T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.7840T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.7816T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.7711T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.7702T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.7663T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.7609T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.7513T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.7483T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.7408T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.7306T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.6937T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

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Calcyphosine-like [Homo sapiens]
Calcyphosine-like [Homo sapiens]
gi|34190100|gb|AAH17586.2|

Protein
OMIM Links for Nucleotide (Select 34190099) (0)
OMIM
PREDICTED: Homo sapiens mannosidase alpha class 2A member 2 (MAN2A2), transcript...
PREDICTED: Homo sapiens mannosidase alpha class 2A member 2 (MAN2A2), transcript variant X16, mRNA
gi|2462544075|ref|XM_054377932.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000602506	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Sep 26, 2016)	germline	clinical testing	Citation Link,
SCV000918472	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Nov 30, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25604157, 25710373, 27443514 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000602506

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(Sep 26, 2016)

germline

clinical testing

Citation Link,

SCV000918472

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Nov 30, 2018)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Citations

PubMed

High-resolution melting (HRM) re-analysis of a polyposis patients cohort reveals previously undetected heterozygous and mosaic APC gene mutations.

Out AA, van Minderhout IJ, van der Stoep N, van Bommel LS, Kluijt I, Aalfs C, Voorendt M, Vossen RH, Nielsen M, Vasen HF, Morreau H, Devilee P, Tops CM, Hes FJ.

Fam Cancer. 2015 Jun;14(2):247-57. doi: 10.1007/s10689-015-9780-5.

PubMed [citation]

PMID:: 25604157
PMCID:: PMC4430602

Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis.

Schwarz RF, Ng CK, Cooke SL, Newman S, Temple J, Piskorz AM, Gale D, Sayal K, Murtaza M, Baldwin PJ, Rosenfeld N, Earl HM, Sala E, Jimenez-Linan M, Parkinson CA, Markowetz F, Brenton JD.

PLoS Med. 2015 Feb;12(2):e1001789. doi: 10.1371/journal.pmed.1001789.

PubMed [citation]

PMID:: 25710373
PMCID:: PMC4339382

See all PubMed Citations (3)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000602506.1

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918472.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: APC c.7786T>G (p.Ser2596Ala) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 276400 control chromosomes, predominantly at a frequency of 8.7e-05 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.22 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.7786T>G has been reported in the literature in individuals affected with colorectal polyps, ovarian and endometrial cancer (Out_2015, Ring_2016, Schwarz_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, six classify as VUS and one classifies as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

#	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: Nov 3, 2024

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