NM_000059.4(BRCA2):c.566A>G (p.Asp189Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 30, 2022
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:: RCV000567705.6

Allele description [Variation Report for NM_000059.4(BRCA2):c.566A>G (p.Asp189Gly)]

NM_000059.4(BRCA2):c.566A>G (p.Asp189Gly)

Gene:

BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.566A>G (p.Asp189Gly)

Other names:

E2571G

HGVS:

NC_000013.11:g.32326548A>G
NG_012772.3:g.16069A>G
NM_000059.4:c.566A>GMANE SELECT
NP_000050.2:p.Asp189Gly
NP_000050.3:p.Asp189Gly
LRG_293t1:c.566A>G
LRG_293:g.16069A>G
LRG_293p1:p.Asp189Gly
NC_000013.10:g.32900685A>G
NM_000059.3:c.566A>G

Nucleotide change:

794A>G

Protein change:

D189G

Links:

dbSNP: rs397507359

NCBI 1000 Genomes Browser:

rs397507359

Molecular consequence:

NM_000059.4:c.566A>G - 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
SCV000673116	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Sep 30, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001347756	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 1, 2019)	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

SCV000673116

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Sep 30, 2022)

germline

clinical testing

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

Citation Link,

SCV001347756

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 1, 2019)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Location of Mutation in BRCA2 Gene and Survival in Patients with Ovarian Cancer.

Labidi-Galy SI, Olivier T, Rodrigues M, Ferraioli D, Derbel O, Bodmer A, Petignat P, Rak B, Chopin N, Tredan O, Heudel PE, Stuckelberger S, Meeus P, Meraldi P, Viassolo V, Ayme A, Chappuis PO, Stern MH, Houdayer C, Stoppa-Lyonnet D, Buisson A, Golmard L, et al.

Clin Cancer Res. 2018 Jan 15;24(2):326-333. doi: 10.1158/1078-0432.CCR-17-2136. Epub 2017 Oct 30.

PubMed [citation]

PMID:: 29084914

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, SCV000673116.5

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

Description

The c.566A>G variant (also known as p.D189G), located in coding exon 6 of the BRCA2 gene, results from an A to G substitution at nucleotide position 566. The aspartic acid at codon 189 is replaced by glycine, an amino acid with similar properties. This alteration was identified in 1 of 353 French and Swiss patients undergoing BRCA1/2 sequencing due to a diagnosis of ovarian cancer (Labidi-Galy SI et al. Clin Cancer Res, 2018 01;24:326-333). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	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, SCV001347756.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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