NM_000059.4(BRCA2):c.8941G>A (p.Glu2981Lys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 26, 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:: RCV000130691.24

Allele description [Variation Report for NM_000059.4(BRCA2):c.8941G>A (p.Glu2981Lys)]

NM_000059.4(BRCA2):c.8941G>A (p.Glu2981Lys)

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.8941G>A (p.Glu2981Lys)

Other names:

p.E2981K:GAA>AAA

HGVS:

NC_000013.11:g.32379503G>A
NG_012772.3:g.69024G>A
NM_000059.4:c.8941G>AMANE SELECT
NP_000050.2:p.Glu2981Lys
NP_000050.3:p.Glu2981Lys
LRG_293t1:c.8941G>A
LRG_293:g.69024G>A
LRG_293p1:p.Glu2981Lys
NC_000013.10:g.32953640G>A
NC_000013.9:g.31851640G>A
NM_000059.3:c.8941G>A
p.E2981K

Protein change:

E2981K

Links:

dbSNP: rs139052578

NCBI 1000 Genomes Browser:

rs139052578

Molecular consequence:

NM_000059.4:c.8941G>A - 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
SCV000185578	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Dec 6, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22703879, 25111659, 29884841, 31550176 Citation Link,
SCV000689159	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 26, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 21318380, 25111659, 28480178, 29884841, 35535289, 35736817, 25741868
SCV002531988	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Dec 20, 2021)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 21318380, 25111659, 29884841 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000185578

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Dec 6, 2019)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000689159

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 26, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV002531988

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Dec 20, 2021)

germline

curation

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, curation

Citations

PubMed

Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.

Johnston JJ, Rubinstein WS, Facio FM, Ng D, Singh LN, Teer JK, Mullikin JC, Biesecker LG.

Am J Hum Genet. 2012 Jul 13;91(1):97-108. doi: 10.1016/j.ajhg.2012.05.021. Epub 2012 Jun 14.

PubMed [citation]

PMID:: 22703879
PMCID:: PMC3397257

Operationalization of Next-Generation Sequencing and Decision Support for Precision Oncology.

Zeng J, Johnson A, Shufean MA, Kahle M, Yang D, Woodman SE, Vu T, Moorthy S, Holla V, Meric-Bernstam F.

JCO Clin Cancer Inform. 2019 Sep;3:1-12. doi: 10.1200/CCI.19.00089. Review.

PubMed [citation]

PMID:: 31550176
PMCID:: PMC6874004

See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV000185578.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

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, SCV000689159.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant replaces glutamic acid with lysine at codon 2981 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant does not impact homology-directed DNA repair activity (PMID: 29884841, 35736817). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 21318380, 28480178, 35535289), and prostate cancer (PMID: 25111659). One of the individuals affected with ovarian cancer also carried a pathogenic variant in the BRCA1 gene, which could explain the observed phenotype (PMID: 35535289). This variant has been identified in 1/242750 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, SCV002531988.1

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

#	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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