NM_000059.4(BRCA2):c.4139_4140dup (p.Lys1381fs) AND Hereditary breast ovarian cancer syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 9, 2022
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:: RCV001385532.15

Allele description [Variation Report for NM_000059.4(BRCA2):c.4139_4140dup (p.Lys1381fs)]

NM_000059.4(BRCA2):c.4139_4140dup (p.Lys1381fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.4139_4140dup (p.Lys1381fs)

Other names:

4366insTT

HGVS:

NC_000013.11:g.32338494_32338495dup
NG_012772.3:g.28015_28016dup
NM_000059.4:c.4139_4140dupMANE SELECT
NM_000059.4:c.4139_4140dupTT
NP_000050.3:p.Lys1381fs
LRG_293:g.28015_28016dup
NC_000013.10:g.32912630_32912631insTT
NC_000013.10:g.32912631_32912632dup
NM_000059.3:c.4139_4140dupTT
NM_000059.4:c.4139_4140dup
U43746.1:n.4366_4367insTT
p.K1381Lfs*8

Protein change:

K1381fs

Links:

Breast Cancer Information Core (BIC) (BRCA2): 4366&base_change=ins TT; dbSNP: rs276174842

NCBI 1000 Genomes Browser:

rs276174842

Molecular consequence:

NM_000059.4:c.4139_4140dup - frameshift variant - [Sequence Ontology: SO:0001589]

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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Pathogen: clinical or host-associated sample from Streptococcus agalactiae
Pathogen: clinical or host-associated sample from Streptococcus agalactiae

biosample
Streptococcus agalactiae strain CH63, whole genome shotgun sequencing project
Streptococcus agalactiae strain CH63, whole genome shotgun sequencing project
gi|1512265612|gb|QYZR00000000.1|QYZ 0000

Nucleotide
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001585415	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 25, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20104584, 20804917, 22366370, 28492532
SCV002512015	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 9, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31209999, 30940100 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001585415

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 25, 2021)

germline

clinical testing

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

SCV002512015

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 9, 2022)

germline

clinical testing

PubMed (2)
[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

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

Novel BRCA1/2 mutations in Serbian breast and breast-ovarian cancer patients with hereditary predisposition.

Dobricić J, Branković-Magić M, Filipović S, Radulović S.

Cancer Genet Cytogenet. 2010 Oct 1;202(1):27-32. doi: 10.1016/j.cancergencyto.2010.06.001.

PubMed [citation]

PMID:: 20804917

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001585415.4

#	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. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant has been reported in individuals affected with breast cancer (PMID: 20804917, 22366370). ClinVar contains an entry for this variant (Variation ID: 51605). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys1381Leufs*8) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product.

#	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, SCV002512015.1

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

Description

Variant summary: BRCA2 c.4139_4140dupTT (p.Lys1381LeufsX8) 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. The variant was absent in 245762 control chromosomes. c.4139_4140dupTT has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Laitman_2019, Gomjec_2019). Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) 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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