NM_000059.4(BRCA2):c.9871del (p.Ser3291fs) AND Hereditary breast ovarian cancer syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 17, 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:: RCV002518785.10

Allele description [Variation Report for NM_000059.4(BRCA2):c.9871del (p.Ser3291fs)]

NM_000059.4(BRCA2):c.9871del (p.Ser3291fs)

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.9871del (p.Ser3291fs)

Other names:

10099delT stop codon 3312

HGVS:

NC_000013.11:g.32398384del
NG_012772.3:g.87905del
NM_000059.4:c.9871delMANE SELECT
NP_000050.3:p.Ser3291fs
LRG_293:g.87905del
NC_000013.10:g.32972519del
NC_000013.10:g.32972521del
NM_000059.3:c.9871delT
NM_000059.4:c.9871del
p.Ser3291fs

Links:

dbSNP: rs886040854

NCBI 1000 Genomes Browser:

rs886040854

Molecular consequence:

NM_000059.4:c.9871del - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003252723	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 17, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 30736435, 18593900, 18607349, 28492532
SCV004039502	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 15, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29446198, 30736435 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003252723

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 17, 2023)

germline

clinical testing

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

SCV004039502

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Aug 15, 2023)

germline

clinical testing

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

Citation Link

Help

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

A syngeneic variance library for functional annotation of human variation: application to BRCA2.

Hucl T, Rago C, Gallmeier E, Brody JR, Gorospe M, Kern SE.

Cancer Res. 2008 Jul 1;68(13):5023-30. doi: 10.1158/0008-5472.CAN-07-6189.

PubMed [citation]

PMID:: 18593900
PMCID:: PMC2536704

Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2.

Kuznetsov SG, Liu P, Sharan SK.

Nat Med. 2008 Aug;14(8):875-81. doi: 10.1038/nm.1719. Epub 2008 Jul 6.

PubMed [citation]

PMID:: 18607349
PMCID:: PMC2640324

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003252723.2

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

Description

This sequence change creates a premature translational stop signal (p.Ser3291Leufs*22) in the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 128 amino acid(s) of the BRCA2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with BRCA2-related conditions (PMID: 30736435). ClinVar contains an entry for this variant (Variation ID: 267176). This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Tyr3308*) have been determined to be pathogenic (PMID: 18593900, 18607349; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004039502.1

#	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.9871delT (p.Ser3291LeufsX22) results in a premature termination codon and is predicted to cause a truncation of the encoded protein, which is a commonly known mechanisms for disease. Although the variant is not predicted to cause absence of the protein through nonsense mediated decay, the variant is predicted to disrupt the last 128 amino acids in the protein sequence. Variants downstream of this position have been classified as pathogenic within ClinVar. The variant was absent in 251214 control chromosomes (gnomAD). c.9871delT has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Rebbeck_2018, Toss_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29446198, 30736435). Six ClinVar submitters have assessed the variant since 2014: all submitters, including one expert panel (ENIGMA) and one consortium (CIMBA), have 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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