NM_000059.4(BRCA2):c.581G>A (p.Trp194Ter) AND Hereditary breast ovarian cancer syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 22, 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:: RCV000044763.18

Allele description [Variation Report for NM_000059.4(BRCA2):c.581G>A (p.Trp194Ter)]

NM_000059.4(BRCA2):c.581G>A (p.Trp194Ter)

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.581G>A (p.Trp194Ter)

HGVS:

NC_000013.11:g.32326563G>A
NG_012772.3:g.16084G>A
NM_000059.4:c.581G>AMANE SELECT
NP_000050.2:p.Trp194Ter
NP_000050.3:p.Trp194Ter
LRG_293t1:c.581G>A
LRG_293:g.16084G>A
LRG_293p1:p.Trp194Ter
NC_000013.10:g.32900700G>A
NM_000059.3:c.581G>A
U43746.1:n.809G>A
p.Trp194*

Nucleotide change:

809G>A

Protein change:

W194*

Links:

dbSNP: rs80358809

NCBI 1000 Genomes Browser:

rs80358809

Molecular consequence:

NM_000059.4:c.581G>A - nonsense - [Sequence Ontology: SO:0001587]

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

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Mus musculus aspartylglucosaminidase (Aga), mRNA
Mus musculus aspartylglucosaminidase (Aga), mRNA
gi|54292134|ref|NM_001005847.1|

Nucleotide
MAG: Desulfobacca sp. 4484_104 ex4484_104_scaffold_154, whole genome shotgun seq...
MAG: Desulfobacca sp. 4484_104 ex4484_104_scaffold_154, whole genome shotgun sequence
gi|1162406394|gb|MUKC01000001.1||gn :MUKC01|ex4484_104_scaffold_154

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000072776	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 22, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8673091, 26577449, 20104584, 28492532
SCV000916896	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 20, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 21719596, 23983145, 8988179, 25652403, 28664506, 8673091, 29446198, 30093976 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000072776

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 22, 2023)

germline

clinical testing

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

SCV000916896

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Nov 20, 2021)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link

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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

BRCA1, BRCA2 and PALB2 mutations and CHEK2 c.1100delC in different South African ethnic groups diagnosed with premenopausal and/or triple negative breast cancer.

Francies FZ, Wainstein T, De Leeneer K, Cairns A, Murdoch M, Nietz S, Cubasch H, Poppe B, Van Maerken T, Crombez B, Coene I, Kerr R, Slabbert JP, Vral A, Krause A, Baeyens A, Claes KB.

BMC Cancer. 2015 Nov 17;15:912. doi: 10.1186/s12885-015-1913-6.

PubMed [citation]

PMID:: 26577449
PMCID:: PMC4647511

Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.

Borg A, Haile RW, Malone KE, Capanu M, Diep A, Törngren T, Teraoka S, Begg CB, Thomas DC, Concannon P, Mellemkjaer L, Bernstein L, Tellhed L, Xue S, Olson ER, Liang X, Dolle J, Børresen-Dale AL, Bernstein JL.

Hum Mutat. 2010 Mar;31(3):E1200-40. doi: 10.1002/humu.21202.

PubMed [citation]

PMID:: 20104584
PMCID:: PMC2928257

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000072776.8

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

Description

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal is associated with altered splicing resulting in unknown protein product impact (Invitae). ClinVar contains an entry for this variant (Variation ID: 51943). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 8673091, 26577449). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp194*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584).

#	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, SCV000916896.2

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

Description

Variant summary: BRCA2 c.581G>A (p.Trp194X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. At least one publication reports experimental evidence that this variant affects mRNA splicing, i.e. increasing exon 4-7 and exon 7 skipping compared to WT (Biswas 2011, Di Giacomo 2013) and can generate a protein albeit with decreased ability to rescue the lethality of BRCA2-null embryonic stem cells (Biswas 2011) and with reduced p53 phosphorylation (Loke 2015).The variant was absent in 251402 control chromosomes. c.581G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as 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

Last Updated: Nov 3, 2024

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