NM_000059.4(BRCA2):c.9945del (p.Glu3316fs) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 8, 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:: RCV000160314.7

Allele description [Variation Report for NM_000059.4(BRCA2):c.9945del (p.Glu3316fs)]

NM_000059.4(BRCA2):c.9945del (p.Glu3316fs)

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.9945del (p.Glu3316fs)

HGVS:

NC_000013.11:g.32398458del
NG_012772.3:g.87979del
NM_000059.4:c.9945delMANE SELECT
NP_000050.2:p.Glu3316fs
NP_000050.3:p.Glu3316fs
LRG_293t1:c.9945del
LRG_293:g.87979del
LRG_293p1:p.Glu3316fs
NC_000013.10:g.32972590del
NC_000013.10:g.32972595del
NM_000059.3:c.9945del
NM_000059.3:c.9945delA
NM_000059.4:c.9945delAMANE SELECT
p.E3316NfsX2
p.K3315KFS*3

Nucleotide change:

10173delA

Protein change:

E3316fs

Links:

dbSNP: rs431825381

NCBI 1000 Genomes Browser:

rs431825381

Molecular consequence:

NM_000059.4:c.9945del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000210805	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Nov 6, 2020)	germline	clinical testing	Citation Link,
SCV004220678	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Aug 8, 2023)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 29337092, 29988080, 10570174, 18317453, 25136594, 16912212, 33479248, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000210805

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Nov 6, 2020)

germline

clinical testing

Citation Link,

SCV004220678

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Aug 8, 2023)

unknown

clinical testing

PubMed (8)
[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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study.

Copson ER, Maishman TC, Tapper WJ, Cutress RI, Greville-Heygate S, Altman DG, Eccles B, Gerty S, Durcan LT, Jones L, Evans DG, Thompson AM, Pharoah P, Easton DF, Dunning AM, Hanby A, Lakhani S, Eeles R, Gilbert FJ, Hamed H, Hodgson S, Simmonds P, et al.

Lancet Oncol. 2018 Feb;19(2):169-180. doi: 10.1016/S1470-2045(17)30891-4. Epub 2018 Jan 11.

PubMed [citation]

PMID:: 29337092
PMCID:: PMC5805863

The functional impact of variants of uncertain significance in BRCA2.

Mesman RLS, Calléja FMGR, Hendriks G, Morolli B, Misovic B, Devilee P, van Asperen CJ, Vrieling H, Vreeswijk MPG.

Genet Med. 2019 Feb;21(2):293-302. doi: 10.1038/s41436-018-0052-2. Epub 2018 Jul 10.

PubMed [citation]

PMID:: 29988080
PMCID:: PMC6752316

See all PubMed Citations (8)

Details of each submission

From GeneDx, SCV000210805.16

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

Description

Frameshift variant predicted to result in protein truncation as the last 103 amino acids are replaced with 1different amino acid; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as c.10173delA; This variant is associated with the following publications: (PMID: 25136594, 16912212)

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004220678.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This variant alters the translational reading frame of the BRCA2 mRNA and is predicted to cause the premature termination of BRCA2 protein synthesis. However, this variant occurs at the end of the BRCA2 transcript and the functional and clinical significance of the residues that would be lost are unknown (PMID: 18317453 (2008), 10570174 (1999) and ENIGMA (https://enigmaconsortium.org/)). In the published literature, this variant has been reported in an individual with breast cancer (PMID: 29337092 (2018)) and in an unaffected individual (PMID: 16912212 (2006)). Published functional studies showed that this variant does not significantly affect BRCA2 protein function (PMID: 29988080 (2019)). The frequency of this variant in the general population, 0.0002 (5/24898 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.

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

Last Updated: Nov 3, 2024

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