rs80359585

Variant names:

• chr13-32340756-ATAACT-A
• rs80359584
• NM_000059.4:c.6405_6409delCTTAA

Variant summary

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

The NM_000059.4(BRCA2):​c.6405_6409delCTTAA​(p.Asn2135LysfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,605,012 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: 0.000021 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:47
• Conservation: PhyloP100: 0.959

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 13-32340756-ATAACT-A is Pathogenic according to our data. Variant chr13-32340756-ATAACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 38043.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340756-ATAACT-A is described in Lovd as [Pathogenic]. Variant chr13-32340756-ATAACT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6405_6409delCTTAA	p.Asn2135LysfsTer3	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.6405_6409delCTTAA	p.Asn2135LysfsTer3	frameshift_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6036_6040delCTTAA	p.Asn2012LysfsTer3	frameshift_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.6405_6409delCTTAA		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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

GnomAD3 exomes AF: 0.00000416 AC: 1 AN: 240630 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130596

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: 0.00

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.0000207 AC: 30 AN: 1452788 Hom.: 0 AF XY: 0.0000208 AC XY: 15 AN XY: 722594

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.0000238

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74382

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

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:47

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:14

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

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

- -

May 24, 2021

Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

-

Institute of Genomics, University of Tartu

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jul 02, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 11, 2015

Institute of Human Genetics, Medical University Innsbruck

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 02, 2020

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 31, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

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

- -

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. -

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

- -

Nov 24, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Asn2135Lysfs*3 variant was identified in 12 of 11758 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian, and prostate cancer (Borg 2010, de Juan 2015, Gayther 1997, Kote-Jarai 2011, Zhang 2011). The variant was also identified in dbSNP (ID: rs80359584) as “With Pathogenic allele”, in ClinVar (classified as pathogenic by Color Genomics, Invitae, GeneDx, Ambry Genetics, SCRP, BIC, and 11 clinical laboratories), COGR, LOVD 3.0, UMD-LSDB (67x causal), BIC Database (13x clinically important), and in ARUP Laboratories (definitely pathogenic). The variant was not identified in Cosmic, or the Zhejiang University Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.6405_6409del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2135 and leads to a premature stop codon at position 2137. 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 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. -

Jul 05, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:12

Jan 15, 2019

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.6405_6409del; p.Asn2135LysfsTer3 variant (rs80359584) is reported in the medical literature in individuals with breast cancer or hereditary breast and ovarian cancer syndrome (Alemar 2016, Deng 2019, Momozawa 2018, Wen 2018, Whitworth 2018). This variant is only observed on one allele (1/240,630 chromosomes) in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting five nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Considering available information, this variant is considered to be pathogenic. References: Alemar B et al. Prevalence of Hispanic BRCA1 and BRCA2 mutations among hereditary breast and ovarian cancer patients from Brazil reveals differences among Latin American populations. Cancer Genet. 2016 Sep;209(9):417-422. PMID: 27425403. Deng M et al. Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China. Int J Cancer. 2019 Sep 15;145(6):1517-1528. PMID: 30720863. Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. PMID: 30287823. Wen WX et al. Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia. J Med Genet. 2018 Feb;55(2):97-103. PMID: 28993434. Whitworth J et al. Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes. Am J Hum Genet. 2018 Jul 5;103(1):3-18. PMID: 29909963. -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: PVS1, PM2, PS4:Moderate -

Jan 30, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM5_strong, PVS1 -

Mar 02, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4 -

Nov 28, 2022

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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 6633_6637delCTTAA and 6633del5; This variant is associated with the following publications: (PMID: 21324516, 21952622, 11179017, 12845657, 10326698, 27425403, 30287823, 34657373, 32980694, 9971877, 8988179, 25863477, 26026974, 25802882, 26687385, 25330149, 26843898, 26439132, 17063270, 18489799, 19967274, 20104584, 24156927, 16684319, 10464601, 12442265, 28127413, 28152038, 28985766, 29161300, 28831036, 28324225, 28724667, 28993434, 29909963, 30720863, 30078507, 30262796, 30720243, 30702160, 31090900, 27741520, 29625052, 26689913, 32318955, 31447099, 32581362, 33646313, 33151324, 34399810, 31825140, 32719484, 30875412, 30787465, 31742824, 33087929, 32359129, 32853339, 32341426, 32438681, 30040829, 35264596, 33804961, 32772980, 32986223) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

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

- -

Sep 19, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.6405_6409del (p.Asn2135Lysfs*3) 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 affected individuals and families with breast and/or ovarian cancer (PMIDs: 36169650 (2022), 33646313 (2021), 33151324 (2021), 32341426 (2020), 32318955 (2020), 31825140 (2019), 31742824 (2020), 31090900 (2019), 30720863 (2019), 30287823 (2018), 30262796 (2018), 30078507 (2018), 29625052 (2018), 29161300 (2017), 28993434 (2018), 28831036 (2017), 28724667 (2017), 28324225 (2017), 27741520 (2016), 27425403 (2016), 21324516 (2011), 18489799 (2008), 17063270 (2007), 11179017 (2001), and 8988179 (1997)). The variant has been reported in breast cancer cases as well as in a control individual in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). It has also been seen in biliary tract cancer (PMID: 36243179 (2022)), prostate cancer (PMIDs: 21952622 (2011) and 32853339 (2021)), and pancreatic cancer (PMID: 34399810 (2021)). The frequency of this variant in the general population, 0.0000042 (1/240630 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:4

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

- -

Jan 14, 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.Asn2135Lysfs*3) 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 (rs80359584, gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 8988179, 11179017, 17063270, 21324516, 21952622, 25802882, 26026974). This variant is also known as c.6402_6406delTAACT, 6630del5, and 6633del5. ClinVar contains an entry for this variant (Variation ID: 38043). For these reasons, this variant has been classified as Pathogenic. -

Apr 24, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asn2135LysfsX3 variant in BRCA2 has been reported in at least 12 individuals with BRCA2-associated cancers (Gayther 1997, Wagner 1999, Risch 2001, Gomes 2007, Machackova 2008, Kote-Jarai 2011, Zhang 2011, de Juan 2015, Hirotsu 2015, Breast Cancer Information Core database:www.research.nhgri.nih.gov/bic/). This variant has also been identified in 1/240630 of pan-ethnic chromosomes by gnomAD (http://gnomad.broadinstitute.org). 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 2135 and leads to a premature termination codon 3 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 autosomal dominant HBOC. In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282424.1). 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, presence in multiple affected individuals and very low frequency in the general population. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2. -

Jan 09, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.6405_6409delCTTAA (p.Asn2135LysfsX3) 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 allele was found at a frequency of 4.2e-06 in 240630 control chromosomes. c.6405_6409delCTTAA has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:4

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. -

Apr 01, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6405_6409delCTTAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 6405 to 6409, causing a translational frameshift with a predicted alternate stop codon (p.N2135Kfs*3). This mutation has been identified in multiple patients and families with hereditary breast and ovarian cancer syndrome (Gayther SA et al. Nat. Genet. 1997 Jan;15:103-5; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Kote-Jarai Z et al. Br. J. Cancer. 2011 Oct;105:1230-4; de Juan I et al. Fam. Cancer. 2015 Dec;14:505-13; Alemar B et al. Cancer Genet. 2016 Sep;209:417-422; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238; Li A et al. Gynecol. Oncol. 2018 10;151(1):145-152). Of note, this alteration is also designated as 6405delCTTAA, 6630del5, and 6633del5 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. -

Mar 08, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 5 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 is also known as c.6402_6406del, 6630del5, and 6633del5 in the literature. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 8988179, 11179017, 17063270, 18489799, 21324516, 25802882, 27425403, 29161300, 30287823). This variant has been identified in 1/240630 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. -

Nov 22, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Breast and/or ovarian cancer Pathogenic:2

Jun 11, 2019

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 17, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related disorder Pathogenic:2

Aug 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.6405_6409del5 variant is predicted to result in a frameshift and premature protein termination (p.Asn2135Lysfs*3). In the literature, this variant may be referred to as N2135fs, 6630del5, 6633_6637delCTTAA, 6633del5, or rs80359584. This variant has been repeatedly reported in individuals with various cancers such as breast, ovarian, prostate, and acute leukemia (reported as 6630del5 in Table 1, Gayther et al. 1997. PubMed ID: 8988179; reported as 6633del5 in Table 1, Risch et al. 2001. PubMed ID: 11179017; Table 2, Lhotova et al. 2020. PubMed ID: 32295079; reported as rs80359584 in Table S3, Darst et al. 2021. PubMed ID: 32853339). This variant has been reported in 1 of over 240,000 individuals in gnomAD, indicating that it is rare. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/38043/). Frameshift variants in BRCA2 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. -

Mar 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6405_6409del;p.(Asn2135Lysfs*3) is a null frameshift variant (NMD) in the BRCA2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 38043; PMID: 21324516) - PS4. This variant is not present in population databases (rs80359584- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inherited breast cancer and ovarian cancer Pathogenic:1

Oct 16, 2024

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1,PM5_Strong -

BRCA2-related cancer predisposition Pathogenic:1

Sep 16, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6405_6409del (p.Asn2135Lysfs*3) variant in the BRCA2 gene is located on the exon 11 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Asn2135Lysfs*3), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast or ovarian cancer (PMID: 36171877, 31706072, 33606809, 30287823). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 38043) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (1/240630). Therefore, the c.6405_6409del (p.Asn2135Lysfs*3) variant of BRCA2 has been classified as pathogenic. -

Breast neoplasm Pathogenic:1

Nov 01, 2015

Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Malignant tumor of pancreas Pathogenic:1

Nov 20, 2017

3DMed Clinical Laboratory Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Familial cancer of breast Pathogenic:1

Mar 03, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast carcinoma Pathogenic:1

Sep 11, 2021

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Mar 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80359584; hg19: chr13-32914893;