rs80359461

Positions:

• chr13-32338981-G-GA
• chr13-32338981-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.4631dup​(p.Asn1544LysfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,216 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:16
• Conservation: PhyloP100: 3.48

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-32338981-G-GA is Pathogenic according to our data. Variant chr13-32338981-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 37912.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.4631dup	p.Asn1544LysfsTer4	frameshift_variant	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.4631dup	p.Asn1544LysfsTer4	frameshift_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250170 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135478

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461216 Hom.: 0 Cov.: 44 AF XY: 0.00000550 AC XY: 4 AN XY: 726910

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: 0.00000720

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 23, 2003	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 15, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 26, 2023	This variant inserts 1 nucleotide in exon 11 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 5 individuals affected with breast or ovarian cancer (PMID: 17688236, 22711857, 23683081, 24728189, 28525389), 1 individual suspected to be affected with Lynch Syndrome and (PMID: 25980754), and has been identified in 9 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 2/276320 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	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
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. -
Pathogenic, no assertion criteria provided	case-control	Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	May 24, 2021	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 19, 2018	Variant summary: BRCA2 c.4631dupA (p.Asn1544LysfsX4) 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 was absent in 245418 control chromosomes (gnomAD). The c.4631dupA variant has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) classify the variant as "pathogenic," in addition, multiple reliable databases also classify the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2023	This sequence change creates a premature translational stop signal (p.Asn1544Lysfs*4) 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 (rs771851449, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast/ovarian cancer, and an individual undergoing testing for Lynch syndrome (PMID: 17688236, 23683081, 24728189, 25980754). This variant is also known as 4859insA. ClinVar contains an entry for this variant (Variation ID: 37912). 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	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2022	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 (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Ramus et al., 2007; Blay et al., 2013; Song et al., 2014); This variant is associated with the following publications: (PMID: 23683081, 26315209, 29922827, 28888541, 17688236, 25980754, 24728189, 30720243, 32719484, 30787465, Celebi_2022_Case Report, Stoganova_2022_Case Report) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 23, 2019	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in affected individuals with breast and/or ovarian cancer in the published literature (PMIDs: 17688236 (2007), 23683081 (2013) and 25980754 (2015)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 16, 2021	The c.4631dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 4631, causing a translational frameshift with a predicted alternate stop codon (p.N1544Kfs*4). This mutation has been identified in multiple European breast and/or ovarian cancer families (Al-Mulla F et al. J. Clin. Pathol. 2009 Apr;62(4):350-6; Ramus SJ et al. Hum Mutat, 2007 Dec;28:1207-15; Blay P et al. BMC Cancer. 2013 May 17;13:243; Song H et al. Hum Mol Genet, 2014 Sep;23:4703-9). This mutation was also detected in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). Of note, this alteration is also designated as 4859insA 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	Dec 11, 2023	This variant inserts 1 nucleotide in exon 11 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 5 individuals affected with breast or ovarian cancer (PMID: 17688236, 22711857, 23683081, 24728189, 28525389), 1 individual suspected to be affected with Lynch Syndrome and (PMID: 25980754), and has been identified in 9 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 2/276320 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. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 23, 2017

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 30, 2024

- -

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: rs80359460; hg19: chr13-32913118;