NM_000059.4(BRCA2):c.8754G>A (p.Glu2918=) AND Hereditary breast ovarian cancer syndrome

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: Jul 7, 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:: RCV000496546.15

Allele description [Variation Report for NM_000059.4(BRCA2):c.8754G>A (p.Glu2918=)]

NM_000059.4(BRCA2):c.8754G>A (p.Glu2918=)

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.8754G>A (p.Glu2918=)

Other names:

E2918E

HGVS:

NC_000013.11:g.32376791G>A
NG_012772.3:g.66312G>A
NM_000059.4:c.8754G>AMANE SELECT
NP_000050.2:p.Glu2918=
NP_000050.3:p.Glu2918=
LRG_293t1:c.8754G>A
LRG_293:g.66312G>A
LRG_293p1:p.Glu2918=
NC_000013.10:g.32950928G>A
NM_000059.3:c.8754G>A
U43746.1:n.8982G>A
p.E2918E

Nucleotide change:

8982G>A

Links:

dbSNP: rs80359803

NCBI 1000 Genomes Browser:

rs80359803

Molecular consequence:

NM_000059.4:c.8754G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Name:: Hereditary breast ovarian cancer syndrome
Synonyms:: Hereditary breast and ovarian cancer syndrome; Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000587968	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR)	no assertion criteria provided	Pathogenic (Jan 31, 2014)	germline	research
SCV001576245	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 7, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17576681, 9536098, 25382762, 22430266, 24145998, 29700634, 31454914, 28492532
SCV002819555	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Dec 15, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22430266, 25382762, 29446198, 29700634, 24145998 Citation Link,
SCV004848891	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (May 15, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 29700634, 31454914, 25382762, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (10)

Details of each submission

From Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR), SCV000587968.1

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

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

From Invitae, SCV001576245.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This variant is present in population databases (rs80359803, gnomAD 0.003%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25382762). ClinVar contains an entry for this variant (Variation ID: 52671). This variant is also known as E2918E. This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22430266, 24145998, 29700634, 31454914). This sequence change affects codon 2918 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA2 protein. This variant also falls at the last nucleotide of exon 21, which is part of the consensus splice site for this exon.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002819555.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: BRCA2 c.8754G>A (p.Glu2918Glu) alters the conserved last nucleotide of exon 21 and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, leading to a shift in the reading frame (Acedo_2015). The variant allele was found at a frequency of 4e-06 in 250952 control chromosomes. c.8754G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Sambiasi_2014 Kaur_2018, Rebbeck_2018, Finkelman_2012). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely 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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848891.1

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

Description

The p.Glu2918Glu variant in BRCA2 has been reported in at least 13 individuals with BRCA2-associated cancers, including at least 1 male with breast cancer, and segregated with disease in 2 affected relatives from 1 family (Kaur 2018 PMID: 29700634, Millan Catalan 2019 PMID: 31454914, Bapat 2021 medRxiv 2021.07.01.21258680; doi: https://doi.org/10.1101/2021.07.01.21258680). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 52671) and was absent from large population studies. Although it is a synonymous (silent) variant, it is located in the last three bases of the exon, which is part of the 5’ splice region. Computational tools predict a splicing impact, which is corroborated by an in vitro minigene assay that indicates that this synonymous change disrupts normal splicing and results in an aberrant transcript that is subjected to nonsense-mediated decay (Acedo 2015 PMID: 25382762). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and ovarian cancer (HBOC). ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP3, PS3_Supporting.

#	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: Jun 9, 2024

ClinVar

Relating variation to medicine