NM_000059.4(BRCA2):c.22_23del (p.Arg8fs) AND Hereditary breast ovarian cancer syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 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:: RCV000043971.19

Allele description [Variation Report for NM_000059.4(BRCA2):c.22_23del (p.Arg8fs)]

NM_000059.4(BRCA2):c.22_23del (p.Arg8fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.22_23del (p.Arg8fs)

HGVS:

NC_000013.10:g.32890615_32890616del
NC_000013.11:g.32316478AG[2]
NG_012772.3:g.5999AG[2]
NG_017006.2:g.3881CT[2]
NM_000059.4:c.22_23delMANE SELECT
NP_000050.3:p.Arg8fs
LRG_293:g.5999AG[2]
NC_000013.10:g.32890615AG[2]
NC_000013.10:g.32890615_32890616del
NC_000013.10:g.32890619_32890620delAG
NG_017006.1:g.472CT[2]
NM_000059.3:c.22_23delAG
p.Arg8Alafs*5
p.Arg8AlafsX5

Nucleotide change:

250delAG

Protein change:

R8fs

Links:

dbSNP: rs397507623

NCBI 1000 Genomes Browser:

rs397507623

Molecular consequence:

NM_000059.4:c.22_23del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000071984	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 22, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 20104584, 15131399, 22762150, 25330149, 25556971, 28492532
SCV000605788	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Aug 5, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15131399, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000071984

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 22, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000605788

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Aug 5, 2016)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	2	2	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Variation in breast cancer risk associated with factors related to pregnancies according to truncating mutation location, in the French National BRCA1 and BRCA2 mutations carrier cohort (GENEPSO).

Lecarpentier J, Noguès C, Mouret-Fourme E, Gauthier-Villars M, Lasset C, Fricker JP, Caron O, Stoppa-Lyonnet D, Berthet P, Faivre L, Bonadona V, Buecher B, Coupier I, Gladieff L, Gesta P, Eisinger F, Frénay M, Luporsi E, Lortholary A, Colas C, Dugast C, Longy M, et al.

Breast Cancer Res. 2012 Jul 3;14(4):R99. doi: 10.1186/bcr3218.

PubMed [citation]

PMID:: 22762150
PMCID:: PMC3680948

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000071984.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change creates a premature translational stop signal (p.Arg8Alafs*5) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 15131399, 22762150, 25330149, 25556971). This variant is also known as c.18_19delAG and 250delAG. ClinVar contains an entry for this variant (Variation ID: 51267). For these reasons, this variant has been 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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000605788.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (2)

Description

The p.Arg8fs variant in BRCA2 has been reported in 1 individual with a BRCA2-ass ociated cancer (Lubinski 2004) and was absent from large population studies, tho ugh the ability of these studies to accurately detect indels may be limited. Thi s variant is predicted to cause a frameshift, which alters the protein?s amino a cid sequence beginning at position 8 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncat ed or absent protein. Heterozygous loss of function of the BRCA2 gene is an esta blished disease mechanism in individuals with hereditary breast and ovarian canc er (HBOC). Furthermore, the p.Arg8fs variant was classified as Pathogenic on Sep tember 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300284 .2). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based on predicted impact to the protei n and absence from controls.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	2	not provided

Last Updated: May 1, 2024

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