NM_000059.4(BRCA2):c.2963A>C (p.Asp988Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Mar 23, 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:: RCV000218795.14

Allele description [Variation Report for NM_000059.4(BRCA2):c.2963A>C (p.Asp988Ala)]

NM_000059.4(BRCA2):c.2963A>C (p.Asp988Ala)

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.2963A>C (p.Asp988Ala)

HGVS:

NC_000013.11:g.32337318A>C
NG_012772.3:g.26839A>C
NM_000059.4:c.2963A>CMANE SELECT
NP_000050.2:p.Asp988Ala
NP_000050.3:p.Asp988Ala
LRG_293t1:c.2963A>C
LRG_293:g.26839A>C
LRG_293p1:p.Asp988Ala
NC_000013.10:g.32911455A>C
NM_000059.3:c.2963A>C

Protein change:

D988A

Links:

dbSNP: rs876659509

NCBI 1000 Genomes Browser:

rs876659509

Molecular consequence:

NM_000059.4:c.2963A>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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Ergolines
Ergolines
A series of structurally-related alkaloids that contain the ergoline backbone structure.<br/>Year introduced: 1969

MeSH
Galantamine
Galantamine
A benzazepine derived from norbelladine. It is found in GALANTHUS and other AMARYLLIDACEAE. It is a cholinesterase inhibitor that has been used to reverse the muscular effects...<br/>Year introduced: 2004(1999)

MeSH
Betacyanins
Betacyanins
Conjugates of betalamic acid with cyclo-dopa, both of which derive from TYROSINE. They appear similar to INDOLES but are biosynthesized by a different path and contain N+. Mem...<br/>Year introduced: 2006

MeSH
Dihydro-beta-Erythroidine
Dihydro-beta-Erythroidine
Dihydro analog of beta-erythroidine, which is isolated from the seeds and other plant parts of Erythrina sp. Leguminosae. It is an alkaloid with curarimimetic properties....<br/>Year introduced: 1991(1975)

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000276064	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 26, 2015)	germline	clinical testing	Citation Link,
SCV003850277	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Dines et al. (Genet Med. 2020))	Likely benign (Mar 23, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000276064

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 26, 2015)

germline

clinical testing

Citation Link,

SCV003850277

University of Washington Department of Laboratory Medicine, University of Washington

criteria provided, single submitter

(Dines et al. (Genet Med. 2020))

Likely benign
(Mar 23, 2023)

germline

curation

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, curation

Citations

PubMed

Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".

Dines JN, Shirts BH, Slavin TP, Walsh T, King MC, Fowler DM, Pritchard CC.

Genet Med. 2020 May;22(5):825-830. doi: 10.1038/s41436-019-0740-6. Epub 2020 Jan 8.

PubMed [citation]

PMID:: 31911673
PMCID:: PMC7200594

Details of each submission

From Ambry Genetics, SCV000276064.5

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

Description

The p.D988A variant (also known as c.2963A>C or 3191A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 2963. The aspartic acid at codon 988 is replaced by alanine, an amino acid with dissimilar properties. This alteration was previously identified in 1/705 bilateral breast cancer cases and 0/1398 unilateral breast cancer cases in a population based study (Borg A et al, Hum. Mutat. 2010 Mar; 31(3):E1200-40). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6496 samples (12992 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort. Based on protein sequence alignment, 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 p.D988A remains unclear.

#	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 University of Washington Department of Laboratory Medicine, University of Washington, SCV003850277.1

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

Description

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

#	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 10, 2024

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