rs80359273

Positions:

• chr13-32332739-CA-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.1265delA​(p.Asn422fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,882 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: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:18
• Conservation: PhyloP100: 2.80

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 (HGNC:):

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 13-32332739-CA-C is Pathogenic according to our data. Variant chr13-32332739-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 37735.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32332739-CA-C is described in Lovd as [Pathogenic]. Variant chr13-32332739-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1265delA	p.Asn422fs	frameshift_variant	10/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.1265delA	p.Asn422fs	frameshift_variant	10/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.896delA	p.Asn299fs	frameshift_variant	10/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.1265delA		non_coding_transcript_exon_variant	9/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151882 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

GnomAD4 exome Cov.: 35

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151882 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74162

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

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2023	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; Observed in individuals with BRCA2-related cancers (Risch et al., 2006; Kote-Jarai et al., 2011; Zhang et al., 2011, Song et al., 2014); Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1493delA; This variant is associated with the following publications: (PMID: 28831036, 21952622, 24728189, 30720243, 29922827, 28888541, 26689913, 21324516, 17148771, 23569316, 27225637, 29625052, 31948886, 30787465, 32090079, 29446198, 20104584) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 21, 2021	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, the variant has been reported in individuals with breast, ovarian, and prostate cancer in the published literature (PMID: 17148771 (2006), 21324516 (2011), 21952622 (2011), 23569316 (2013), 24728189 (2014), 29625052 (2018)). This variant has not been reported in large, multi-ethnic general populations. Based on the available information, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 27, 2020	The BRCA2 c.1265delA; p.Asn422fs variant (rs80359273), also known as 1493delA, has been reported in multiple individuals with prostate or ovarian cancers (Kote-Jarai 2011, Risch 2006, Song 2014, Zhang 2011). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant introduces a frameshift, and is predicted to result in a truncated protein or an absent transcript. Based on available information, the p.Asn422fs variant is classified as pathogenic. References: Kote-Jarai Z et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011; 105(8):1230-4. Risch H et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst. 2006; 98(23):1694-706. Song H et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Genet. 2014 Sep 1;23(17):4703-9. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011; 121(2):353-7. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 11, 2019	- -

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4

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)	Mar 13, 2012	- -
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 breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change creates a premature translational stop signal (p.Asn422Ilefs*8) 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 (rs757511530, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ovarian cancer and prostate cancer (PMID: 17148771, 21324516, 21952622, 23569316, 24728189). This variant is also known as 1493delA. ClinVar contains an entry for this variant (Variation ID: 37735). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 07, 2022	Variant summary: BRCA2 c.1265delA (p.Asn422IlefsX8) 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 248930 control chromosomes (gnomAD). c.1265delA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer (examples: Risch_2006, , Kote-Jarai_2011, Song_2014 and NHGRI BIC database). These data indicate that the variant is very likely to be associated with disease. One expert panel and eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 08, 2023	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 been reported in 4 individuals affected with breast or ovarian cancer (PMID: 8640236, 17148771, 21324516, 24728189, 29625052). This variant has been identified in 1/240472 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	Jun 18, 2024	The c.1265delA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1265, causing a translational frameshift with a predicted alternate stop codon (p.N422Ifs*8). This mutation has been reported in multiple patients with breast, ovarian, or prostate cancer (Risch HA et al. J. Natl. Cancer Inst. 2006 Dec;98:1694-706; Kote-Jarai Z et al. Br. J. Cancer 2011 Oct;105:1230-4; Castro E et al. J. Clin. Oncol. 2013 May;31(14):1748-57; Song H et al. Hum. Mol. Genet. 2014 Sep 1;23(17):4703-9; Lu C et al. Nat Commun. 2015 Dec 22;6:10086; Maxwell KN et al. Nat Commun, 2017 08;8:319). Of note, this alteration is also designated as 1493delA and c.1262delA 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	curation	Sema4, Sema4	Aug 10, 2021	- -

BRCA2-related cancer predisposition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Mar 28, 2024

The c.1265del (p.Asn422Ilefs*8) variant in the BRCA2 gene is located on the exon 10 and is predicted to result in shift of reading frame that introduces a premature translation termination codon (p.Asn422Ilefs*8), resulting in an absent or disrupted protein product. Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 29446198, 11897832, 8988179). This variant has been reported in multiple individuals with breast/ovarian/prostate cancer (PMID: 21952622, 29446198, 24728189). The variant is reported in ClinVar as pathogenic (ID: 37735) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.1265del (p.Asn422Ilefs*8) variant of BRCA2 has been classified as pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 26, 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: rs80359273; hg19: chr13-32906876;