NM_000038.6(APC):c.2845A>G (p.Met949Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 21, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000129130.18

Allele description [Variation Report for NM_000038.6(APC):c.2845A>G (p.Met949Val)]

NM_000038.6(APC):c.2845A>G (p.Met949Val)

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.2845A>G (p.Met949Val)

HGVS:

NC_000005.10:g.112838439A>G
NG_008481.4:g.150919A>G
NM_000038.6:c.2845A>GMANE SELECT
NM_001127510.2:c.2845A>G
NM_001127510.3:c.2845A>G
NM_001127511.3:c.2791A>G
NM_001354895.2:c.2845A>G
NM_001354896.2:c.2899A>G
NM_001354897.2:c.2875A>G
NM_001354898.2:c.2770A>G
NM_001354899.2:c.2761A>G
NM_001354900.2:c.2722A>G
NM_001354901.2:c.2668A>G
NM_001354902.2:c.2572A>G
NM_001354903.2:c.2542A>G
NM_001354904.2:c.2467A>G
NM_001354905.2:c.2365A>G
NM_001354906.2:c.1996A>G
NP_000029.2:p.Met949Val
NP_001120982.1:p.Met949Val
NP_001120983.2:p.Met931Val
NP_001341824.1:p.Met949Val
NP_001341825.1:p.Met967Val
NP_001341826.1:p.Met959Val
NP_001341827.1:p.Met924Val
NP_001341828.1:p.Met921Val
NP_001341829.1:p.Met908Val
NP_001341830.1:p.Met890Val
NP_001341831.1:p.Met858Val
NP_001341832.1:p.Met848Val
NP_001341833.1:p.Met823Val
NP_001341834.1:p.Met789Val
NP_001341835.1:p.Met666Val
LRG_130:g.150919A>G
NC_000005.9:g.112174136A>G
NM_000038.5:c.2845A>G
NM_000038.6:c.2845A>G
p.M949V

Protein change:

M666V

Links:

dbSNP: rs587781348

NCBI 1000 Genomes Browser:

rs587781348

Molecular consequence:

NM_000038.6:c.2845A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.2845A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.2791A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.2845A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.2899A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.2875A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.2770A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.2761A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.2722A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.2668A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.2572A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.2542A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.2467A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.2365A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.1996A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000183848	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Uncertain significance (Jul 6, 2021)	germline	clinical testing	Citation Link,
SCV000686915	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 21, 2023)	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

SCV000183848

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Uncertain significance
(Jul 6, 2021)

germline

clinical testing

Citation Link,

SCV000686915

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 21, 2023)

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	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

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, SCV000183848.7

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

Description

The p.M949V variant (also known as c.2845A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 2845. The methionine at codon 949 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

From Color Diagnostics, LLC DBA Color Health, SCV000686915.4

#	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 methionine with valine at codon 949 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 not been identified 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

Last Updated: Apr 15, 2024

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