rs80359629

chr13-32346830-CAATA-C

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.6944_6947del(p.Ile2315LysfsTer12) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000206 in 1,453,294 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. T2314T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 5.26

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 13-32346830-CAATA-C is Pathogenic according to our data. Variant chr13-32346830-CAATA-C is described in ClinVar as [Pathogenic]. Clinvar id is 38075.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32346830-CAATA-C is described in Lovd as [Pathogenic]. Variant chr13-32346830-CAATA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.6944_6947del	p.Ile2315LysfsTer12	frameshift_variant	13/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.6944_6947del	p.Ile2315LysfsTer12	frameshift_variant	13/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000801 AC: 2 AN: 249558 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134970

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453294 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 723148

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: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5

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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 29, 2012	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 22, 2014	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The p.Ile2315LysfsX12 variant in BRCA2 has been reported in at least 15 families with breast and/or ovarian cancer (Frank 1998, Wong-Brown 2015, Evans 2008, Teer 2016, BIC database). It has also been identified in 2/113008 European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2315 and leads to a premature termination codon 12 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: 91435). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Strong. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change creates a premature translational stop signal (p.Ile2315Lysfs*12) 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 present in population databases (rs751065688, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 9667259, 25682074). This variant is also known as 7172del4. ClinVar contains an entry for this variant (Variation ID: 38075). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 01, 2021	Variant summary: BRCA2 c.6944_6947delTAAA (p.Ile2315LysfsX12) 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. The variant allele was found at a frequency of 8e-06 in 249558 control chromosomes (gnomAD). c.6944_6947delTAAA has been reported in the literature in multiple individuals affected with breast and ovarian cancer (example: Frank_1998, Evans_2008, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Seven other ClinVar submitters including an expert panel (ENIGMA) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 30, 2021	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been identified in individuals with breast and ovarian cancer in the published literature (PMID: 9667259 (1998), 29446198 (2018), 25682074 (2015), 17636422 (2008)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2021	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Frank 1998, Evans 2008, Wong-Brown 2015, Huang 2018); Also known as 7172del4 and 7172delTAAA; This variant is associated with the following publications: (PMID: 29625052, 9667259, 17636422, 25682074, 28852190, 24307375, 28152038, 20167696, 30720243) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 19, 2022	The c.6944_6947delTAAA pathogenic mutation, located in coding exon 12 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 6944 to 6947, causing a translational frameshift with a predicted alternate stop codon (p.I2315Kfs*12). This mutation has been reported in multiple individuals with hereditary breast and/or ovarian cancer (Evans D et al. Fam. Cancer. 2008 Jul;7:113-7; Frank T et al. J. Clin. Oncol. 1998 Jul;16:2417-25; Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150(1):71-80; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Of note, this alteration is also designated as 7172del4 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 26, 2023	This variant deletes 4 nucleotides 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 is also known as 7172del4 or 7172delTAAA in the literature. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 9667259, 17636422, 25682074) and has been identified in 13 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 2/249558 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80359629; hg19: chr13-32920967;