rs746229647

chr13-32338200-CTG-C

Variant summary

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

The NM_000059.4(BRCA2):c.3847_3848del(p.Val1283LysfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000407 in 1,549,192 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. T1282T) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:49 O:1
• Conservation: PhyloP100: 0.523

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 13-32338200-CTG-C is Pathogenic according to our data. Variant chr13-32338200-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 37859.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338200-CTG-C is described in Lovd as [Pathogenic]. Variant chr13-32338200-CTG-C is described in Lovd as [Pathogenic]. Variant chr13-32338200-CTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.3847_3848del	p.Val1283LysfsTer2	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.3847_3848del	p.Val1283LysfsTer2	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000724 AC: 11 AN: 151948 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000538 AC: 11 AN: 204502 Hom.: 0 AF XY: 0.0000537 AC XY: 6 AN XY: 111628

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: 0.000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000372 AC: 52 AN: 1397244 Hom.: 0 AF XY: 0.0000361 AC XY: 25 AN XY: 691682

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000843

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000445

Gnomad4 OTH exome AF: 0.0000347

GnomAD4 genome AF: 0.0000724 AC: 11 AN: 151948 Hom.: 0 Cov.: 33 AF XY: 0.0000674 AC XY: 5 AN XY: 74202

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000491

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:49 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:19

Pathogenic, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 31, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Sep 23, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Feb 21, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 26, 2023	Criteria applied: PVS1,PS4,PM2_SUP -
Pathogenic, criteria provided, single submitter	curation	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Apr 12, 2019	- -
Pathogenic, criteria provided, single submitter	literature only	Counsyl	Aug 25, 2014	- -
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. -
Pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, Medical University Innsbruck	Feb 11, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Apr 04, 2017	The c.3847_3848del (p.Val1283Lysfs*2) variant has been detected in several patients and families with breast and/or ovarian cancer [PMID 8589730, 22752604, 24504028, 22006311, 21324516, sometimes reported as 4075delGT], colorectal cancer [PMID 24814045] and prostate cancer [PMID 21952622]. This variant has been reported in 11 heterozygous individuals from the ExAC population database (http://exac.broadinstitute.org/variant/13-32912337-CTG-C). This 2 bp deletion is located in exon 11, and leads to the creation of a frameshift and a premature stop codon at amino acid position. This variant is expected to result in a loss of function of the protein and is thus classified as pathogenic. This pathogenic variant in the BRCA2 gene is also considered medically actionable [ACMG59, PMID 27854360] -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jun 06, 2023	A known pathogenic mutations was detected in the BRCA2 ( c.3847_3848delGT). This sequence change creates a premature translational stop signal (p.Val1283Lysfs*2) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs746229647, ExAC 0.02%). This variant has been reported in several individuals and families affected with breast, ovarian, and prostate cancer (PMID: 8589730, 21324516, 23199084, 21952622). It was also shown to segregate with disease in a family with colorectal and other cancers (PMID: 24814045). This variant is also known as 4075delGT in the literature. ClinVar contains an entry for this variant (Variation ID: 37859). ClinVar classifies this variant as Pathogenic, 3 stars (expert panel, 39 submissions), citing 22 articles (33372952, 29752822, 29321669, 28324225, 26681312 and 17 more). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The c.3847_3848del (p.Val1283LysfsTer2) frameshift variant in BRCA2 gene has been reported in several individuals and families affected with breast, ovarian, and prostate cancer (Zhang et al., 2011; Janavičius 2010). It was also shown to segregate with disease in a family with colorectal and other cancers (Garre et al., 2015). This variant is reported with the allele frequency (0.005%) in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Valine 1283, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Val1283LysfsTer2. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (Borg et al., 2010). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 15, 2023	The c.3847_3848del (p.Val1283Lysfs*2) in the BRCA2 gene is located on the exon 11 and is predicted to result in reading frameshift from the codon 1283 and introduce a premature translation termination codon (p.Val1283Lysfs*2), leading to an absent or disrupted protein product. Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832). This variant was reported in more than 10 unrelated individuals with breast/ovarian/prostate cancer (PMID: 32164353, 29325860, 24814045, 32824581, 33670479, 32778078, 33801055, 32923906). It is one of the frequently observed BRCA2 variants in Caucasian and Jewish populations (PMID: 34022715, 29446198). The variant is reported in ClinVar as pathogenic (ID: 37859). The variant is rare in the general population according to gnomAD (12/235838). Therefore, the c.3847_3848del (p.Val1283Lysfs*2) variant of BRCA2 has been classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 21, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -

not provided Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	BRCA2: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 28, 2023	The BRCA2 c.3847_3848del (p.Val1283Lysfs*2) 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 multiple individuals and families affected with breast/ovarian cancer (PMIDs: 18489799 (2008), 19016756 (2008), 24156927 (2014), 28324225 (2017), 29752822 (2018), 34657373 (2022)), colorectal cancer (PMID: 29321669 (2018)), pancreatic cancer (PMID: 34399810 (2021)), prostate cancer (PMID: 32853339 (2021)), and rhabdomyosarcoma (PMID: 33372952 (2020)). The frequency of this variant in the general population, 0.000098 (11/112032 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	Jun 29, 2020	PVS1, PM2, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	May 21, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This is a deletion of two base pairs from exon 11 of the BRCA2 mRNA (c.3847_3848delGT), causing a frameshift at codon 1283. This creates a novel stop codon 2 amino acid residues later and is expected to result in a truncated, non-functional protein. Truncating variants in BRCA2 are known to be pathogenic. This variant is also known as 4075delGT in the literature and it has been reported in several individuals and families affected with breast, ovarian, and prostate cancer (PMID 21952622, 21324516, 23199084). It was also shown to segregate with disease in a family with colorectal and other cancers (PMID: 24814045). The mutation database ClinVar contains entries for this variant, where it is listed as pathogenic (Variation ID: 37859). -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 30, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	The BRCA2 c.3847_3848del; p.Val1283LysfsTer2 variant (rs80359405), also known as 4075delGT, is published in the medical literature in individuals with several types of cancer and families with HBOC (Borg 2010, Garre 2015, Susswein 2016, Wojcik 2016). This variant is reported in ClinVar (Variation ID: 37859) and is classified as pathogenic by the evidence-based network for the interpretation of germline mutant alleles (ENIGMA) expert panel (see link to ENIGMA consortium classification criteria). This variant is found in the general population with an overall allele frequency of 0.0051% (12/235838 alleles) in the Genome Aggregation Database. This variant deletes two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Link to ENIGMA classification criteria: https://enigmaconsortium.org/library/general-documents/enigma-classification-criteria/ Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. Garre P et al. BRCA2 gene: a candidate for clinical testing in familial colorectal cancer type X. Clin Genet. 2015 Jun;87(6):582-7. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. Wojcik P et al. Recurrent mutations of BRCA1, BRCA2 and PALB2 in the population of breast and ovarian cancer patients in Southern Poland. Hered Cancer Clin Pract. 2016 Feb 3;14:5. -

Hereditary breast ovarian cancer syndrome Pathogenic:4

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	Invitae	Jan 30, 2024	This sequence change creates a premature translational stop signal (p.Val1283Lysfs*2) 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 (rs746229647, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, colorectal, prostate and other cancers (PMID: 8589730, 21324516, 21952622, 23199084, 24814045). It is commonly reported in individuals of Scandanavian ancestry (PMID: 23199084). This variant is also known as 4075delGT. ClinVar contains an entry for this variant (Variation ID: 182328, 37859). 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	Jun 22, 2015	Variant summary: This frameshift variant leads to premature truncation at exon 11. In ExAC, it has been observed at allele frequency of 11/94102 chromosomes. This frequency is lower than the maximal expected allele frequency for a pathogenic BRCA2 variant based on the disease prevalence of HBOC. It has been recurrently observed in patients with HBOC. This supports that the 11 individuals with this variant in ExAC are very likely to represent as subclinical cases and/or reduced penetrance. Multiple labs (via ClinVar) classify the variant as pathogenic. Therefore, based on the variant's nature and location, and population and patient data, this has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 19, 2023	The p.Val1283LysfsX2 variant in BRCA2 has been reported in >35 individuals with BRCA2-associated cancers (Wang 2012 PMID:21643751, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/). This variant has also been identified in 0.013% (9/67984) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). 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 1283 and leads to a premature termination codon 2 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 for HBOC. Additionally, this variant was classified as pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 37859). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP criteria applied: PS4, PM2_Supporting, PVS1. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 08, 2021	The c.3847_3848delGT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 3847 to 3848, causing a translational frameshift with a predicted alternate stop codon (p.V1283Kfs*2). This mutation has been detected in numerous families with breast, ovarian, pancreatic, and/or prostate cancer (Tavtigian SV et al. Nat. Genet. 1996 Mar;12:333-7; Hahn SA et al. J. Natl. Cancer Inst. 2003 Feb;95:214-21; Janaviius R. EPMA J. 2010 Sep;1:397-412; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Kote-Jarai Z et al. Br. J. Cancer. 2011 Oct;105:1230-4; Meisel C et al. Arch Gynecol Obstet. 2017 May;295:1227-1238; El Ansari FZ et al. BMC Cancer. 2020. Aug 10;20(1):747; Heramb C et al. Hered Cancer Clin Pract. 2018 Jan 10;16:3). This mutation was also reported in one family diagnosed with familial colorectal cancer type X (FCCX) that had no alteration detected in the mismatch repair (MMR) pathway (Garre P et al. Clin. Genet. 2015 Jun;87:582-7). Of note, this alteration is also designated as 4075delGT 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 05, 2022	This variant deletes 2 nucleotides 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 observed in many individuals and families affected with breast and ovarian cancer (PMID: 8589730, 10790213, 17574839, 18465347, 18489799, 19016756, 19620486, 20104584, 21324516, 22752604, 23479189, 24156927, 24528374, 24728189, 28324225, 29752822, 33471991) and is reported as a common cause of hereditary breast and ovarian cancer in Norwegian and Danish populations (PMID: 23199084). This variant has been identified in 12/235838 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	Jan 06, 2022	- -

Breast and/or ovarian cancer Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 06, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	CZECANCA consortium	Jun 11, 2019	- -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2014	This variant is denoted BRCA2 c.3847_3848delGT at the cDNA level and p.Val1283LysfsX2 (V1283KfsX2) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AACT{delGT}AAGT. The deletion causes a frameshift, which changes a Valine to a Lysine at codon 1283 in exon 11, and creates a premature stop codon at position 2 of the new reading frame. This mutation is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.3847_3848delGT, previously reported as 4075delGT, has been reported in association with breast and ovarian cancer (Tavtigian 1996). BRCA2 c.3847_3848delGT is also a common mutation in Norwegian and Danish populations (Janavicius 2010). We therefore consider this mutation to be pathogenic. and is indicative of Hereditary Breast and Ovarian Cancer (HBOC) syndrome, an autosomal dominant condition that predisposes to breast and ovarian cancer as well as other cancers. The predominant BRCA2-related cancer risks for women who have not been diagnosed with cancer have been estimated as 41% - 84% lifetime risk for breast cancer and 11% - 27% lifetime risk for ovarian cancer (Ford 1998, Risch 2006). BRCA2 mutations have also been reported in women with fallopian tube carcinoma, primary peritoneal carcinoma, and uterine serous carcinoma (Levine 2003, Biron-Shental 2006). Women with BRCA1/2 mutations also have an increased risk for contralateral breast cancer. Women with BRCA mutations whose first cancer was diagnosed under age 40 have a 21-31% risk to develop a second breast cancer within 10 years and a 63% risk to develop a second breast cancer within 25 years. Women with BRCA mutations whose first cancer was diagnosed between ages 40 and 50 have an 11-13% risk to develop a second breast cancer within 10 years and a 44-49% risk within 25 years. Women with BRCA mutations whose first cancer was diagnosed after age 50 have an 8% risk to develop a second breast cancer within 10 years and a 20% risk within 25 years (Graeser 2009). Other cancer risks associated with a BRCA2 mutation include up to a 7% risk for pancreatic cancer (Ozcelik 1997, The Breast Cancer Linkage Consortium 1999), up to a 34% risk for prostate cancer in male carriers (Thompson 2001), and up to a 7% risk for male breast cancer (Liede 2004). The variant is found in BRCA,HIRISK-BR-HEREDIC,BR-OV-HEREDIC panel(s). -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 30, 2022

- -

Rhabdomyosarcoma Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Sep 01, 2020

- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Breast carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Sep 12, 2021

- -

Neoplasm of ovary Pathogenic:1

Pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

BRCA2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2024

The BRCA2 c.3847_3848delGT variant is predicted to result in a frameshift and premature protein termination (p.Val1283Lysfs*2). This variant, also documented as 4075delGT in the literature, has been reported in individuals with breast and/or ovarian cancer (Tavtigian et al. 1996. PubMed ID: 8589730; Zhang et al. 2011. PubMed ID: 21324516; Janavičius. 2010. PubMed ID: 23199084). This variant was also found to segregate with cancer in a family with colorectal cancer type X and prostate cancer (Garre et al. 2015. PubMed ID: 24814045), and it was reported in an additional individual with a personal and family history of prostate cancer (Kote-Jarai et al. 2011. PubMed ID: 21952622). This variant is reported in 0.0098% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been reported in the ClinVar database as pathogenic and reviewed by an expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/37859/). In summary, this variant is interpreted as pathogenic. -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Val1283Lysfs*2 variant was identified in 15 of 4576 proband chromosomes (frequency: 0.003) from individuals or families with breast, ovarian, or pancreatic cancer (Claes 1999, Claus 2005, Hahn 2003, Lubinski 2004, Risch 2001, Singer 2014, Soegaard 2008, Sugano 2008). The variant was also identified in several databases, including: dbSNP (ID: rs80359405) “With pathogenic allele”, COGR (classified as pathogenic by a clinical laboratory), COSMIC, BIC (64x, classified as pathogenic), ARUP Laboratories BRCA Mutations Database, and ClinVar (classified as pathogenic by Ambry Genetics, Counsyl, GeneDx, Division of Human Genetics Innsbruck – Medical University Innsbruck, Sharing Clinical Reports Project, Invitae, and BIC). The variant was identified in control databases in 1 of 199586 chromosomes at a frequency of 0.000005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 1 of 14726 chromosomes (freq: 0.00007); it was not observed in the South Asian, African, Other, Latino, Ashkenazi Jewish, or Finnish populations. The BRCA2, c.3847_3848delGT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1283 and leads to a premature stop codon at position 1284. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Hereditary breast ovarian cancer syndrome;C1838457:Fanconi anemia complementation group D1 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Pathogenic and reported on 06-26-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

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: rs80359405; hg19: chr13-32912337;