NM_000059.4(BRCA2):c.994del (p.Ile332fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 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:: RCV000574932.17

Allele description [Variation Report for NM_000059.4(BRCA2):c.994del (p.Ile332fs)]

NM_000059.4(BRCA2):c.994del (p.Ile332fs)

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.994del (p.Ile332fs)

Other names:

1222delA

HGVS:

NC_000013.10:g.32906603del
NC_000013.11:g.32332472del
NG_012772.3:g.21993del
NM_000059.4:c.994delMANE SELECT
NP_000050.3:p.Ile332fs
LRG_293:g.21993del
NC_000013.10:g.32906603del
NC_000013.10:g.32906609del
NC_000013.10:g.32906609delA
NM_000059.3:c.994delA
NM_000059.4:c.994delA
U43746.1:n.1222delA
p.Ile332Phefs*17

Links:

Breast Cancer Information Core (BIC) (BRCA2): 1222&base_change=del A; dbSNP: rs80359777

NCBI 1000 Genomes Browser:

rs80359777

Molecular consequence:

NM_000059.4:c.994del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Hereditary neoplastic syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000661202	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 8, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10506595, 22798144, 26187060, 28205045, 29446198, 31825140 Citation Link,
SCV000684103	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 15, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000661202

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 8, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV000684103

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 15, 2020)

germline

clinical testing

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

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

BRCA1/BRCA2 germline mutations in locally recurrent breast cancer patients after lumpectomy and radiation therapy: implications for breast-conserving management in patients with BRCA1/BRCA2 mutations.

Turner BC, Harrold E, Matloff E, Smith T, Gumbs AA, Beinfield M, Ward B, Skolnick M, Glazer PM, Thomas A, Haffty BG.

J Clin Oncol. 1999 Oct;17(10):3017-24.

PubMed [citation]

PMID:: 10506595

Characteristics and spectrum of BRCA1 and BRCA2 mutations in 3,922 Korean patients with breast and ovarian cancer.

Kim H, Cho DY, Choi DH, Choi SY, Shin I, Park W, Huh SJ, Han SH, Lee MH, Ahn SH, Son BH, Kim SW; Korean Breast Cancer Study Group, Haffty BG.

Breast Cancer Res Treat. 2012 Aug;134(3):1315-26. doi: 10.1007/s10549-012-2159-5. Epub 2012 Jul 14.

PubMed [citation]

PMID:: 22798144

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000661202.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The c.994delA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 994, causing a translational frameshift with a predicted alternate stop codon (p.I332Ffs*17). This alteration has been detected in multiple families with breast and/or ovarian cancer (Turner BC et al, J. Clin. Oncol. 1999 Oct; 17(10):3017-24; Kim H et al. Breast Cancer Res. Treat., 2012 Aug;134:1315-26; Park B et al. Breast Cancer Res. Treat., 2017 May;163:139-150; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). Of note, this alteration is also designated as 1222delA in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000684103.3

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

Description

This variant deletes 1 nucleotide in exon 10 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is 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: May 16, 2025

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