rs11571658

Variant names:

• chr13-32340629-CTT-C
• rs11571658
• NM_000059.4:c.6275_6276delTT

Variant summary

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

The NM_000059.4(BRCA2):​c.6275_6276delTT​(p.Leu2092ProfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000691 in 1,606,550 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 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:50 U:1
• Conservation: PhyloP100: 0.862

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 13-32340629-CTT-C is Pathogenic according to our data. Variant chr13-32340629-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 9318.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340629-CTT-C is described in Lovd as [Pathogenic]. Variant chr13-32340629-CTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6275_6276delTT	p.Leu2092ProfsTer7	frameshift_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.6275_6276delTT	p.Leu2092ProfsTer7	frameshift_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.5906_5907delTT	p.Leu1969ProfsTer7	frameshift_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.6275_6276delTT		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000370 AC: 9 AN: 243532 Hom.: 0 AF XY: 0.0000304 AC XY: 4 AN XY: 131786

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000609

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.0000449

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.0000736 AC: 107 AN: 1454378 Hom.: 0 AF XY: 0.0000664 AC XY: 48 AN XY: 723256

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000464

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000564

Gnomad4 NFE exome AF: 0.0000901

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:50 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:18

Jan 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 12, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.6275_6276del (p.Leu2092Profs*7) variant in exon 11 of the BRCA2 gene is a deletion of 2 nucleotides and is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. This particular variant (also known as 6503delTT) has been reported in multiple individuals affected with breast, ovarian, and prostate cancer (PMID: 8524414, 22009639, 21324516, 22006311, 20736950, 23199084). The c.6275_6276del (p.Leu2092Profs*7) variant in BRCA2 gene is classified as pathogenic (Atteeq Rehman 10-12-2017). -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 18, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2018

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 18, 2014

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

May 27, 2024

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1; PM5_PTC_Strong -

Oct 16, 2013

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 24, 2014

Pathway Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 22, 2024

Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Null variant (frame-shift) in gene BRCA2, predicted to cause NMD. Loss-of-function is a known mechanism of disease (PVS1).Combined evidence strength is Very Strong (score = 12).Very Strong: ClinVar classifies this variant as Pathogenic, 3 stars. Strong: LOVD classifies this variant as Pathogenic (PP5). GnomAD genomes homozygous allele count = 0 is less than 2 for AD/AR gene BRCA2,GnomAD exomes homozygous allele count = 0 is less than 2 for AD/AR gene BRCA2 (PM2).We observed this variant in a 37-year-old woman with malignant breast cancer and a family history of breast cancer. -

Apr 22, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Variant allele predicted to encode a truncated non-functional protein. -

Jul 26, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.6275_6276del (p.Leu2092ProfsTer7) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay. This variant has been reported in several individuals with breast and/or ovarian cancer (PMID: 11359068, 21324516, 22006311, 22009639, 26026974, 26041759, 27153395, 29335925, 29566657). It has a maximum subpopulation frequency of 0.0059% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant is also known as 6503delTT in the literature. In summary, this variant meets criteria to be classified as pathogenic. -

Mar 02, 2020

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2017

Genologica Medica

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 24, 2021

Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

not provided Pathogenic:13 Uncertain:1

May 04, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in multiple individuals with a personal or family history consistent with pathogenic variants in this gene (Wooster 1995, Edwards 2010, Walsh 2011, Zhang 2011, Bayraktar 2012, Higgs 2015); Also known as 6503delTT; This variant is associated with the following publications: (PMID: 16644204, 26026974, 20002770, 22460208, 10782928, 17850627, 10090482, 15131399, 28392550, 26295337, 29566657, 30630528, 30267214, 24830819, 26041759, 22009639, 22006311, 21324516, 20736950, 8524414, 26843898, 25330149, 16616110, 21993507, 17636422, 26586665, 25884701, 20104584, 14984974, 24156927, 23479189, 20859677, 11039575, 9585608, 9792861, 11453973, 11359068, 10486320, 16905680, 15689453, 17591843, 9537231, 16079000, 11179017, 27225637, 27356891, 28127413, 28301456, 27836010, 27153395, 25085752, 28918466, 12955716, 12698193, 9585613, 12161611, 10227398, 8896551, 23199084, 11597388, 29335925, 29422015, 29915322, 29909963, 30720243, 30322717, 30093976, 31090900, 30612635, 29945567, 32255556, 29625052, 31447099) -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 25, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 16, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals with hereditary breast and ovarian cancer (PMID: 27153395 (2016), 11359068 (2001), 12955716 (2003), 21324516 (2011), 22006311 (2011), 22009639 (2012), 23199084 (2010), 26026974 (2015), 26041759 (2015), 29566657 (2018), 29625052 (2018), 8524414 (1995)), male breast cancer (PMID: 29335925(2018)) and prostate cancer (PMID: 20736950 (2010), 29915322 (2018)). In a large scale breast cancer association study, the variant was observed among the breast cancer cases as well as in unaffected individuals (PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.000081 (4/49646 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Jun 17, 2015

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 30, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP5, PM5, PVS1 -

Nov 07, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.6275_6276del; p.Leu2092ProfsTer7 variant (rs11571658, ClinVar Variation ID: 9318), also known as 6503delTT in traditional nomenclature, is reported in multiple individuals with a personal and/or family history of breast, ovarian, or prostate cancer (Bayraktar 2012, de Juan 2015, Edwards 2010, Tea 2014, Wang 2018, Walsh 2011, Wooster 1995, Zhang 2011). This variant is found in the general population with a low overall allele frequency of 0.004% (10/274924 alleles) in the Genome Aggregation Database (v2.1.1). This variant causes a frameshift by deleting 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: Bayraktar S et al. Predictive factors for BRCA1/BRCA2 mutations in women with ductal carcinoma in situ. Cancer. 2012 Mar 15;118(6):1515-22. PMID: 22009639. de Juan I et al. BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study. Fam Cancer. 2015 Dec;14(4):505-13. PMID: 26026974. Edwards SM et al. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 2010 Sep 7;103(6):918-24. PMID: 20736950. Tea MK et al. Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer. Maturitas. 2014 Jan;77(1):68-72. PMID: 24156927. Wang YA et al. Germline breast cancer susceptibility gene mutations and breast cancer outcomes. BMC Cancer. 2018 Mar 22;18(1):315. PMID: 29566657. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. PMID: 22006311. Wooster R et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995 Dec 21-28;378(6559):789-92. PMID: 8524414. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7. PMID: 21324516. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2018

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: PVS1, PM2, PS4:Moderate -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:7

Apr 18, 2017

Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BRCA2 c.6275_6276delTT (p.Leu2092Profs) variant 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.N2135fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/120912 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in numerous Br/Ov cancer patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Apr 20, 2017

Department of Pathology and Molecular Medicine, Queen's University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 06, 2021

National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu2092ProfsX7 variant in BRCA2 has been reported >100 individuals with BRCA2-associated cancer (Breast Information Core Database (BIC)); Bayraktar 2012, de Juan 2015, Edwards 2010, Fostira 2018, Mijuskovic 2018, Walsh 2011, Wang 2018, Whitworth 2018, Wooster 1995, Zhang 2011). In addition, the p.Leu2080X variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282422.1) and has been suggested to be a European founder mutation (Janavicius 2010). This variant has been identified in 0.005% (6/124234) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org. It is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2092 and leads to a premature termination codon 7 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 hereditary breast and ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS4, PM2. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu2092Profs*7) 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 (rs11571658, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 8524414, 20736950, 21324516, 22006311, 22009639, 23199084). It is commonly reported in individuals of European ancestry (PMID: 23199084). This variant is also known as 6503delTT. ClinVar contains an entry for this variant (Variation ID: 9318). For these reasons, this variant has been classified as Pathogenic. -

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Familial cancer of breast Pathogenic:3

Mar 10, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PM5_STR -

Nov 14, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Nov 27, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6275_6276delTT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 2 nucleotides between positions 6275 and 6276, causing a translational frameshift with a predicted alternate stop codon (p.L2092Pfs*7). This mutation has been detected in multiple individuals with breast and/or ovarian cancer (Khitto G et al. Hum. Hered. 2001;52:55-8; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Bayraktar S et al. Cancer. 2012 Mar;118:1515-22; Higgs JE et al. J. Med. Genet. 2015 Sep;52:642-5; de Juan I et al. Fam. Cancer. 2015 Dec;14:505-13; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-817; Fostira F et al. Breast Cancer Res. Treat. 2018 May;169:105-113; Wang YA et al. BMC Cancer. 2018 03;18:315). Of note, this alteration is also designated as 6503delTT in some 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. -

Jan 26, 2018

Academic Department of Medical Genetics, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -

Jan 03, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 dozens of individuals affected with breast and/or ovarian cancer and is a common disease-causing mutation in the European population (PMID: 21324516, 23199084, 23479189, 24156927, 26026974, 29566657). This variant also has been detected in a breast cancer case-control meta-analysis in 30/60463 cases and 5/53461 unaffected individuals with odds ratio of 5.307 (95% CI 2.059 to 13.679) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000156). This variant has been identified in 10/274924 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:2

Aug 18, 2015

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 06, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related cancer predisposition Pathogenic:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 dozens of individuals affected with breast and/or ovarian cancer and is a common disease-causing mutation in the European population (PMID: 21324516, 23199084, 23479189, 24156927, 26026974, 29566657). This variant also has been detected in a breast cancer case-control meta-analysis in 30/60463 cases and 5/53461 unaffected individuals with odds ratio of 5.307 (95% CI 2.059 to 13.679) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000156). This variant has been identified in 10/274924 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. -

BRCA2-related disorder Pathogenic:1

May 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.6275_6276delTT variant is predicted to result in a frameshift and premature protein termination (p.Leu2092Profs*7). This variant, also known as c.6503delTT and rs11571658 in the literature, has been reported in individuals with breast and ovarian cancer (see, for example, Bayraktar et al. 2012. PubMed ID: 22009639; Table S1, Carter et al. 2018. PubMed ID: 30322717; de Juan et al. 2015. PubMed ID: 26026974), pancreatic cancer (Young et al. 2018. PubMed ID: 29945567), and prostate cancer (Table S3, Darst et al. 2021. PubMed ID: 32853339). This variant is reported in 0.0059% of alleles in individuals of Latino descent in gnomAD and is classified as pathogenic in the ClinVar database by several other clinical laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/9318/). Taken together, this variant is classified as pathogenic. -

Medulloblastoma;C0346153:Familial cancer of breast;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C2931456:Familial prostate cancer;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1

Apr 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Endometrial carcinoma Pathogenic:1

Feb 21, 2023

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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: rs11571658; hg19: chr13-32914766; COSMIC: COSV99061623;