rs398122772

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000059.4(BRCA2):c.3873delA(p.Gln1291HisfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000361 in 1,384,266 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q1291Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:12U:1

Conservation

PhyloP100: 0.255

Publications

5 publications found

Variant links:

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
Fanconi anemia complementation group D1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
pancreatic cancer, susceptibility to, 2
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
medulloblastoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-32338226-CA-C is Pathogenic according to our data. Variant chr13-32338226-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 91809.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.3873delA	p.Gln1291HisfsTer2	frameshift_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
BRCA2	ENST00000380152.8 link	c.3873delA	p.Gln1291HisfsTer2	frameshift_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7 link	c.3504delA	p.Gln1168HisfsTer2	frameshift_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2 link	n.3873delA		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000361

AC:

AN:

1384266

Hom.:

Cov.:

AF XY:

0.00000292

AC XY:

AN XY:

684042

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30220

American (AMR)

AF:

0.00

AC:

AN:

31560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23364

East Asian (EAS)

AF:

0.00

AC:

AN:

38528

South Asian (SAS)

AF:

0.00

AC:

AN:

75576

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51204

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5434

European-Non Finnish (NFE)

AF:

0.00000467

AC:

AN:

1071374

Other (OTH)

AF:

0.00

AC:

AN:

57006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary breast ovarian cancer syndrome

Pathogenic:4

Oct 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Gln1291HisfsX2 variant in BRCA2 (also referred to in the literature as c.4101delA) has been reported in at least 3 individuals with BRCA2-related cancers (Young 2018, Song 2014, Foley 2015). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1291 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Sept 8 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 91809). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting. -

Apr 25, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRCA2 c.3873delA (p.Gln1291HisfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 194150 control chromosomes. c.3873delA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Apr 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gln1291Hisfs*2) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and skin cancer (PMID: 26023681). This variant is also known as 4101delA. ClinVar contains an entry for this variant (Variation ID: 91809). For these reasons, this variant has been classified as Pathogenic. -

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:3

Sep 08, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

Variant allele predicted to encode a truncated non-functional protein. -

Oct 25, 2011

Sharing Clinical Reports Project (SCRP)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Nov 08, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3873delA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 3873, causing a translational frameshift with a predicted alternate stop codon (p.Q1291Hfs*2). In one case control study, this mutation was detected in 1/2222 individuals with invasive epithelial ovarian cancer and 0/1528 matched controls (Song H et al. Hum. Mol. Genet., 2014 Sep;23:4703-9). Another study identified this mutation, referred to as 4101delA, in a female patient diagnosed with breast cancer at ages 28, 39, and 55 then with skin cancer at age 55 (Foley SB et al. EBioMedicine, 2015 Jan;2:74-81). This mutation has also been detected in a patient with pancreatic cancer (Young EL et al. BMC Cancer, 2018 Jun;18:697). 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. -

Jan 02, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant deletes 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4101delA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast, ovarian, and pancreatic cancer (PMID: 24728189, 26023681, 29945567, Color internal data). 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. -

not provided

Pathogenic:1Uncertain:1

Feb 14, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast and skin cancer (PMID: 26023681 (2015)), ovarian cancer (PMID: 24728189 (2014)), and pancreatic cancer (PMID: 29945567 (2018)). Based on the available information, this variant is classified as pathogenic. -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

BRCA2-related cancer predisposition

Pathogenic:1

Jun 09, 2024

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Familial cancer of breast

Pathogenic:1

Dec 15, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.26

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over