rs80359470

Positions:

• chr13-32339228-GAA-G
• chr13-32339228-GAA-GAAA

Variant summary

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

The NM_000059.4(BRCA2):​c.4876_4877del​(p.Asn1626SerfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,612,998 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 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:22 O:1
• Conservation: PhyloP100: 0.250

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 13-32339228-GAA-G is Pathogenic according to our data. Variant chr13-32339228-GAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 37929.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339228-GAA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.4876_4877del	p.Asn1626SerfsTer12	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.4876_4877del	p.Asn1626SerfsTer12	frameshift_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152066 Hom.: 0 Cov.: 33

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000801 AC: 2 AN: 249578 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135274

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: 0.0000185 AC: 27 AN: 1460932 Hom.: 0 AF XY: 0.0000179 AC XY: 13 AN XY: 726732

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: 0.0000225

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152066 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74266

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 08, 2023	This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4874_4875delAA, 4877delAA, 5102delAA, and 5104delAA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 7 individuals affected with ovarian cancer (PMID 26681312, 24728189, 22006311, 20609468, 11179017, Color internal data), 7 individuals affected with prostate cancer (PMID: 29915322, 27989354, 24556621, 23524863, 21952622, Color internal data), 5 individuals affected with breast cancer (PMID: 28087643, 28503720, 28008555, 26787237, Color internal data), and 1 individual affected with pancreatic cancer (Color internal data). In a large breast cancer case-control study, this variant was observed in 1/60466 cases and 1/53461 controls (Leiden Open Variation Database DB-ID BRCA2_003713 PMID: 33471991). This variant has been identified in 2/249578 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, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
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)	Jun 04, 2012	- -
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)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Apr 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 15, 2023	The BRCA2 c.4876_4877del (p.Asn1626Serfs*12) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals affected with ovarian cancer (PMIDs: 11179017 (2001), 36169650 (2022)), breast cancer (PMIDs: 28503720 (2017), 33302456 (2020), 33113089 (2021)), prostate cancer (PMIDs: 27989354 (2017), 29915322 (2018), 30340782 (2019), 32853339 (2021)), renal cell carcinoma (PMID: 35441217 (2022)), acute lymphoblastic leukemia (ALL) (PMID: 29489754 (2018)), and colorectal cancer (PMID: 34761457 (2022)). It has been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). The frequency of this variant in the general population, 0.000008 (2/249578 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 12, 2023	PP5, PM2, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2020	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; Also known as 5102delAA or 5104delAA; This variant is associated with the following publications: (PMID: 28503720, 24082139, 29684080, 26681312, 28087643, 30720243, 23524863, 23242139, 11179017, 24556621, 21952622, 26787237, 17148771, 21324516, 15131399, 22006311, 28008555, 30340782, 29489754, 31325073, 29915322, 27989354, 31447099) -

Hereditary breast ovarian cancer syndrome Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 15, 2021	The p.Asn1626SerfsX12 variant in BRCA2 has been reported in >20 individuals with BRCA2-associated cancers (Risch 2001 PMID:11179017, Kote-Jarai 2011 PMID:21952622, Gonzalez-Garay 2013 PMID:24082139, Leongamornlert 2014 PMID:24556621, Meric-Bernstam 2016 PMID:26787237, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/). This variant has also been identified in 0.003% (2/67992) European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1). 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 1626 and leads to a premature termination codon 12 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 ovarian cancer (HBOC). Additionally, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variant ID 37929). In summary, the p.Asn1626fs variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP criteria applied: PS4, PM2_Supporting, PVS1. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 27, 2017	Variant summary: The BRCA2 c.4876_4877delAA (p.Asn1626Serfs) variant (alternatively also known as 5102delAA) results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g. p.Val1814X, p.Lys1872X, p.Cys1885X, etc.). This variant is absent in 122720 control chromosomes (including ExAC). This variant has been reported in several HBOC patients in literature and clinical databases. It has also been reported in patients with prostate cancer (Kote-Jarai_2011). In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is 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, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change creates a premature translational stop signal (p.Asn1626Serfs*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 (rs80359470, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 11179017, 21952622, 23524863, 24556621, 26787237, 28008555). This variant is also known as c.4874_4875delAA, 4877delAA, 5102delAA, and 5104delAA. ClinVar contains an entry for this variant (Variation ID: 37929). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 29, 2023	This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4874_4875delAA, 4877delAA, 5102delAA, and 5104delAA 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 ovarian cancer (PMID 26681312, 24728189, 22006311, 20609468, 11179017, Color internal data), prostate cancer (PMID: 29915322, 27989354, 24556621, 23524863, 21952622, Color internal data), breast cancer (PMID: 28087643, 28503720, 28008555, 26787237, Color internal data), and an individual affected with pancreatic cancer (Color internal data). This variant has been identified in 2/249578 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	curation	Sema4, Sema4	Mar 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 21, 2021	The c.4876_4877delAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 4876 and 4877, causing a translational frameshift with a predicted alternate stop codon (p.N1626Sfs*12). This mutation has been described in multiple families with breast, ovarian, melanoma, and/or prostate cancer (Lubinski J et al. Fam Cancer, 2004;3:1-10; Audeh MW et al. Lancet, 2010 Jul;376:245-51; Zhang S et al. Gynecol Oncol, 2011 May;121:353-7; Sandhu SK et al. Ann Oncol, 2013 May;24:1416-8; Leongamornlert D et al. Br. J. Cancer, 2014 Mar;110:1663-72; Song H et al. Hum Mol Genet, 2014 Sep;23:4703-9; Meric-Bernstam F et al. Ann Oncol, 2016 05;27:795-800; Rummel SK et al. Breast Cancer Res Treat, 2017 Aug;164:593-601; Na R et al. Eur Urol, 2017 05;71:740-747; Afghahi A et al. Clin Cancer Res, 2017 07;23:3365-3370; Pritzlaff M et al. Breast Cancer Res Treat, 2017 02;161:575-586; Mijuskovic M et al. Br J Cancer, 2018 07;119:96-104; Gröbner SN et al. Nature, 2018 03;555:321-327; Zafeiriou Z et al. Eur Urol, 2019 01;75:184-192; Lovejoy LA et al. Genes (Basel), 2020 12;11; Dorling et al. N Engl J Med. 2021 02;384:428-439; Lattimore V et al. Breast Cancer Res Treat, 2021 Feb;185:583-590). Of note, this alteration is also designated as 5102delAA, 5104delAA, 4877delAA, c.4876_4877del, and c.4874_4875delAA 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. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 12, 2015

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 17, 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: rs80359470; hg19: chr13-32913365;