NM_000059.4(BRCA2):c.9777del (p.Ile3259fs) AND Hereditary breast ovarian cancer syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 8, 2021
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:: RCV000826190.16

Allele description [Variation Report for NM_000059.4(BRCA2):c.9777del (p.Ile3259fs)]

NM_000059.4(BRCA2):c.9777del (p.Ile3259fs)

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.9777del (p.Ile3259fs)

HGVS:

NC_000013.11:g.32398290del
NG_012772.3:g.87811del
NM_000059.4:c.9777delMANE SELECT
NM_000059.4:c.9777delT
NP_000050.3:p.Ile3259fs
LRG_293:g.87811del
NC_000013.10:g.32972426del
NC_000013.10:g.32972427del
NC_000013.10:g.32972427delT
NM_000059.3:c.9777del
NM_000059.3:c.9777delT
NM_000059.4:c.9777del
p.Ile3259MetfsX16

Protein change:

I3259fs

Links:

dbSNP: rs1593201815

NCBI 1000 Genomes Browser:

rs1593201815

Molecular consequence:

NM_000059.4:c.9777del - 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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Metagenome-assembled genome: ERR2762153_binner123_Refined_27
Metagenome-assembled genome: ERR2762153_binner123_Refined_27

biosample
Metagenome-assembled genome: ERR2762182_binner13_Refined_2
Metagenome-assembled genome: ERR2762182_binner13_Refined_2

biosample

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000967737	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Feb 26, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002232531	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 8, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17026620, 18593900, 18607349, 22711857, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000967737

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Feb 26, 2019)

germline

clinical testing

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

SCV002232531

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 8, 2021)

germline

clinical testing

PubMed (5)
[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	unknown	1	1	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

Inherited association of breast and colorectal cancer: limited role of CHEK2 compared with high-penetrance genes.

Naseem H, Boylan J, Speake D, Leask K, Shenton A, Lalloo F, Hill J, Trump D, Evans DG.

Clin Genet. 2006 Nov;70(5):388-95.

PubMed [citation]

PMID:: 17026620

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967737.2

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

Description

The p.Ile3259MetfsX16 variant in BRCA2 has not been previously reported in individuals with BRCA2-associated cancers or in large population studies. This variant is predicted to cause a frameshift, which alters the proteinâ€™s amino acid sequence beginning at position 3259 and leads to a premature termination codon 16 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD), resulting in a truncated protein. However, loss of function variants 3' to this variant have been reported in patients with hereditary breast and/or ovarian cancer (HBOC) and have been classified as pathogenic by an expert panel in ClinVar. In summary the p.Ile3259MetfsX16 variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner, based upon predicted impact to the protein and absence from the general population. ACMG/AMP criteria applied: PSV1_Strong, PM2.

#	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		1	not provided	1	not provided

From Invitae, SCV002232531.3

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

Description

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Tyr3308*) have been determined to be pathogenic (PMID: 17026620, 18593900, 18607349, 22711857). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 667416). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This sequence change creates a premature translational stop signal (p.Ile3259Metfs*16) in the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 160 amino acid(s) of the BRCA2 protein.

#	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: Jul 23, 2024

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