NM_000059.4(BRCA2):c.4103del (p.Leu1368fs) AND Hereditary breast ovarian cancer syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 11, 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:: RCV000507796.16

Allele description [Variation Report for NM_000059.4(BRCA2):c.4103del (p.Leu1368fs)]

NM_000059.4(BRCA2):c.4103del (p.Leu1368fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.4103del (p.Leu1368fs)

HGVS:

NC_000013.10:g.32912594del
NC_000013.11:g.32338458del
NG_012772.3:g.27979del
NM_000059.4:c.4103delMANE SELECT
NP_000050.2:p.Leu1368fs
NP_000050.3:p.Leu1368fs
LRG_293t1:c.4103del
LRG_293:g.27979del
LRG_293p1:p.Leu1368fs
NC_000013.10:g.32912594del
NC_000013.10:g.32912595del
NC_000013.10:g.32912595delT
NM_000059.3:c.4103del
NM_000059.3:c.4103delT
p.(Leu1368TyrfsTer6)
p.Leu1368TyrfsX6

Protein change:

L1368fs

Links:

dbSNP: rs1555283552

NCBI 1000 Genomes Browser:

rs1555283552

Molecular consequence:

NM_000059.4:c.4103del - 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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Synthetic construct Mus musculus clone IMAGE:9093392 insulinoma-associated 2 (Insm2) gene, partial cds
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Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000605812	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Dec 23, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001385133	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 11, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20104584, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000605812

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Dec 23, 2016)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001385133

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 11, 2022)

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	1	1	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

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

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 (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000605812.2

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

Description

The p.Leu1368fs variant in BRCA2 has not been previously reported in individuals with hereditary breast or ovarian cancer (HBOC) and was absent from large popul ation studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 1368 and leads to a prematu re termination codon 6 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of func tion of the BRCA2 gene is an established disease mechanism in HBOC. In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autoso mal dominant manner.

#	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		1	not provided	1	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001385133.3

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

Description

This sequence change creates a premature translational stop signal (p.Leu1368Tyrfs*6) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 440456). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency).

#	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: Oct 26, 2024

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