rs754611265

chr13-32346886-G-GT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):c.6998dup(p.Pro2334ThrfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,607,758 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. V2333V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: -0.0760

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 13-32346886-G-GT is Pathogenic according to our data. Variant chr13-32346886-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 219496.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.6998dup	p.Pro2334ThrfsTer6	frameshift_variant	13/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.6998dup	p.Pro2334ThrfsTer6	frameshift_variant	13/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152008 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249368 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455750 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 724248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152008 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74246

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 06, 2023	This variant inserts 1 nucleotide in exon 13 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 been reported in individuals affected with breast, ovarian, or pancreatic cancer (PMID: 27194814, 28423363, 29928469, 34680878, Color internal data) and has been identified in five families among the CIMBA participants (PMID: 29446198). This variant has been identified in 1/249368 chromosomes 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 17, 2023	The c.6998dupT pathogenic mutation, located in coding exon 12 of the BRCA2 gene, results from a duplication of T at nucleotide position 6998, causing a translational frameshift with a predicted alternate stop codon (p.P2334Tfs*6). This alteration has been detected in patients with breast and/or ovarian cancer and in a large, worldwide study of BRCA1/2 mutation positive families (Winter C et al. Ann. Oncol., 2016 08;27:1532-8; Tedaldi G et al. Oncotarget, 2017 Jul;8:47064-47075; Maksimenko J et al. Hered Cancer Clin Pract, 2018 Jun;16:12; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). Additionally, this alteration has been detected in 0/3030 patients with pancreatic cancer and 1/123136 controls (Hu C et al. JAMA, 2018 06;319:2401-2409). 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 10, 2023	This variant is present in population databases (rs754611265, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 27194814). ClinVar contains an entry for this variant (Variation ID: 219496). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Pro2334Thrfs*6) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 20, 2017	The p.Pro2334ThrfsX6 variant in BRCA2 has been reported in 1 individual with bre ast cancer (Winter 2016) and has been identified in 1/111078 European chromosome s by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein?s ami no acid sequence beginning at position 2334 and leads to a premature termination codon 6 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in individuals with hereditary breast and ovari an cancer (HBOC). In addition, this variant was classified as Pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000301119.2). I n summary, this variant meets criteria to be classified as pathogenic for HBOC i n an autosomal dominant manner based upon the predicted impact to the protein an d absence from the general population. ACMG/AMP criteria applied: PVS1, PM2. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2018

The c.6998dupT variant in the BRCA2 gene has been seen in at least two women with breast cancer (Winter et al., 2016; Tedaldi et al., 2017). The duplication causes a frameshift which changes a Proline to a Threonine at codon 2334, and creates a premature stop codon at position 6 of the new reading frame, denoted Pro2334ThrfsX6. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs754611265; hg19: chr13-32921023;