NM_000038.6(APC):c.1904G>C (p.Gly635Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Oct 16, 2023
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:: RCV000491278.18

Allele description [Variation Report for NM_000038.6(APC):c.1904G>C (p.Gly635Ala)]

NM_000038.6(APC):c.1904G>C (p.Gly635Ala)

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.1904G>C (p.Gly635Ala)

Other names:

p.G635A:GGA>GCA

HGVS:

NC_000005.10:g.112835111G>C
NG_008481.4:g.147591G>C
NM_000038.6:c.1904G>CMANE SELECT
NM_001127510.3:c.1904G>C
NM_001127511.3:c.1850G>C
NM_001354895.2:c.1904G>C
NM_001354896.2:c.1958G>C
NM_001354897.2:c.1934G>C
NM_001354898.2:c.1829G>C
NM_001354899.2:c.1820G>C
NM_001354900.2:c.1781G>C
NM_001354901.2:c.1727G>C
NM_001354902.2:c.1631G>C
NM_001354903.2:c.1601G>C
NM_001354904.2:c.1526G>C
NM_001354905.2:c.1424G>C
NM_001354906.2:c.1055G>C
NP_000029.2:p.Gly635Ala
NP_001120982.1:p.Gly635Ala
NP_001120983.2:p.Gly617Ala
NP_001341824.1:p.Gly635Ala
NP_001341825.1:p.Gly653Ala
NP_001341826.1:p.Gly645Ala
NP_001341827.1:p.Gly610Ala
NP_001341828.1:p.Gly607Ala
NP_001341829.1:p.Gly594Ala
NP_001341830.1:p.Gly576Ala
NP_001341831.1:p.Gly544Ala
NP_001341832.1:p.Gly534Ala
NP_001341833.1:p.Gly509Ala
NP_001341834.1:p.Gly475Ala
NP_001341835.1:p.Gly352Ala
LRG_130t1:c.1904G>C
LRG_130:g.147591G>C
NC_000005.9:g.112170808G>C
NM_000038.4:c.1904G>C
NM_000038.5:c.1904G>C

Protein change:

G352A

Links:

dbSNP: rs730881239

NCBI 1000 Genomes Browser:

rs730881239

Molecular consequence:

NM_000038.6:c.1904G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.1904G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.1850G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.1904G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.1958G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.1934G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.1829G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.1820G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.1781G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.1727G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.1631G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.1601G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.1526G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.1424G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.1055G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000579853	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Oct 16, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000681494	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 10, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002531086	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Feb 12, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000579853

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Oct 16, 2023)

germline

clinical testing

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

Citation Link,

SCV000681494

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 10, 2023)

germline

clinical testing

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

SCV002531086

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Feb 12, 2022)

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

Rates of Actionable Genetic Findings in Individuals with Colorectal Cancer or Polyps Ascertained from a Community Medical Setting.

Gordon AS, Rosenthal EA, Carrell DS, Amendola LM, Dorschner MO, Scrol A, Stanaway IB, DeVange S, Ralston JD, Zouk H, Rehm HL, Larson E, Crosslin DR, Leppig KA, Jarvik GP.

Am J Hum Genet. 2019 Sep 5;105(3):526-533. doi: 10.1016/j.ajhg.2019.07.012. Epub 2019 Aug 15.

PubMed [citation]

PMID:: 31422818
PMCID:: PMC6731361

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 Ambry Genetics, SCV000579853.6

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

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000681494.5

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

Description

This missense variant replaces glycine with alanine at codon 635 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 2/282734 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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

From Sema4, Sema4, SCV002531086.1

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

Last Updated: May 1, 2024

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