VCV000009342.90 - ClinVar

NM_000059.4(BRCA2):c.658_659del (p.Val220fs)

Germline

Top reviewed classifications are shown here.

Submission summary:

51 submissions

43 submitters

17 conditions

Reviewed by expert panel

Pathogenic

Apr 2016 by Evidence-based…

for Breast-ovarian cancer, familial, susceptibility to, 2

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000059.4(BRCA2):c.658_659del (p.Val220fs)

Variation ID: 9342 Accession: VCV000009342.90

Type and length

Deletion, 2 bp

Location

Cytogenetic: 13q13.1 13: 32329468-32329469 (GRCh38) [ NCBI UCSC ] 13: 32903605-32903606 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 29, 2015	Oct 20, 2024	Apr 22, 2016

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.658_659del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Val220fs	frameshift
NM_000059.3:c.657_658del
NM_000059.3:c.658_659delGT
NC_000013.11:g.32329469_32329470del
NC_000013.10:g.32903606_32903607del
NG_012772.3:g.18990_18991del
LRG_293:g.18990_18991del
U43746.1:n.886_887delGT

... more HGVS ... less HGVS

Protein change

Other names

886_887delGT
886delGT

Canonical SPDI

NC_000013.11:32329467:TGT:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

Breast Cancer Information Core (BIC) (BRCA2): 886&base_change=del GT ClinGen: CA024188 OMIM: 600185.0027 dbSNP: rs80359604 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
BRCA2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	-	-

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Medulloblastoma	Pathogenic (2)	criteria provided, single submitter	Oct 29, 2021	RCV000009932.16
Fanconi anemia complementation group D1	Pathogenic (1)	no assertion criteria provided	Jan 1, 2007	RCV000009929.13
Wilms tumor 1	Pathogenic (2)	criteria provided, single submitter	Oct 29, 2021	RCV000009930.14
Glioma susceptibility 3	risk factor (1)	no assertion criteria provided	Jan 1, 2007	RCV000009931.13
Breast-ovarian cancer, familial, susceptibility to, 2	Pathogenic (14)	reviewed by expert panel	Apr 22, 2016	RCV000031637.30
Hereditary breast ovarian cancer syndrome	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 29, 2024	RCV000044988.30
not provided	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Dec 1, 2023	RCV000074548.61
Hereditary cancer-predisposing syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 11, 2023	RCV000131858.22
Breast-ovarian cancer, familial, susceptibility to, 1	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 2, 2020	RCV000210073.13
Familial cancer of breast	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 26, 2024	RCV000466729.12
Breast and/or ovarian cancer	Pathogenic (2)	no assertion criteria provided	Jun 11, 2019	RCV000735587.10
Malignant tumor of breast	Pathogenic (1)	no assertion criteria provided	-	RCV001356991.10
Malignant tumor of prostate	Pathogenic (1)	criteria provided, single submitter	Oct 29, 2021	RCV001843452.9
Breast-ovarian cancer, familial, susceptibility to, 2 Familial cancer of breast Fanconi anemia complementation group D1 Glioma susceptibility 3 Malignant tumor of prostate Medulloblastoma Pancreatic cancer, susceptibility to, 2 Wilms tumor 1	Pathogenic (1)	criteria provided, single submitter	Oct 29, 2021	RCV002496316.8
Uterine corpus cancer	Pathogenic (1)	no assertion criteria provided	Feb 21, 2023	RCV003128126.8
BRCA2-related disorder	Pathogenic (2)	criteria provided, single submitter	-	RCV003335024.3
Gastric cancer	Pathogenic (1)	no assertion criteria provided	Jul 1, 2021	RCV003162226.8
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 22, 2016)	reviewed by expert panel (ENIGMA BRCA1/2 Classification Criteria (2015)) Method: curation	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Accession: SCV000282430.1 First in ClinVar: Jun 24, 2016 Last updated: Jun 24, 2016	Comment: Variant allele predicted to encode a truncated non-functional protein.
Pathogenic (Jul 10, 2014)	criteria provided, single submitter (HA_assertions_20150911) Method: research	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: unknown	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: CSER-HudsonAlpha Accession: SCV000584073.1 First in ClinVar: Nov 05, 2016 Last updated: Nov 05, 2016	Number of individuals with the variant: 1
Pathogenic (Sep 21, 2015)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000744390.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal unknown) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447718.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Breast carcinoma (present) Sex: female
Pathogenic (Nov 18, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449833.1 First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020	Number of individuals with the variant: 3
Pathogenic (Feb 10, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002536247.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The BRCA2 c.658_659delGT (p.V220Ifs4) variant has been reported in heterozygosity in numerous individuals with breast, ovarian, and prostate cancer (PMID: 29446198, 9667259, 33478551, 27741520, 31112363, … (more) The BRCA2 c.658_659delGT (p.V220Ifs4) variant has been reported in heterozygosity in numerous individuals with breast, ovarian, and prostate cancer (PMID: 29446198, 9667259, 33478551, 27741520, 31112363, 32875559, 23767878, 32098980). This variant has also been reported in compound heterozygosity in several individuals with Fanconi anemia, complementation group D1 (PMID: 14670928, 26657402). It is also known as c.886_887delGT and c.886delGT in the literature. This variant is a well-established pathogenic variant associated with hereditary breast and ovarian cancer syndrome (PMID: 29446198 ). This variant causes a frameshift at amino acid 220 that results in premature termination 4 amino acids downstream. At this location, this is predicted to cause nonsense-mediated decay and result in an absent protein (loss of function). Loss of function variants in BRCA1 or BRCA2 are known to be pathogenic (PMID: 29446198). This variant was observed in 3/23770 chromosomes in the African/African American population, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). Based on the current evidence available, this variant is interpreted as pathogenic. (less)	Publications: PubMed (10) PubMed: 29446198‚ 9667259‚ 33478551‚ 27741520‚ 31112363‚ 32875559‚ 23767878‚ 32098980‚ 14670928‚ 26657402
Pathogenic (Oct 02, 2015)	criteria provided, single submitter (CIMBA Mutation Classification guidelines May 2016) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge Accession: SCV000327465.4 First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022
Pathogenic (Apr 18, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000494408.2 First in ClinVar: Sep 04, 2016 Last updated: Dec 11, 2022	Publications: PubMed (6) PubMed: 12373604‚ 18703817‚ 24156927‚ 18465347‚ 22798144‚ 26657402 Comment: Variant summary: The c.658_659delGT variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein, which is a commonly known … (more) Variant summary: The c.658_659delGT variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.755_758delACAG, p.Asp252fsX24; c.771_775delTCAAA, p.Asn257fsX17; c.778_779delGA, p.Glu260fsX15). The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.006% which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). The variant has been reported in numerous affected individuals in the literature, including 2 siblings affected with Fanconi anemia who also carried a second pathogenic BRCA2 variant (Svojgr_2016). Mutliple reputable clinical labs have classified the variant as "Pathogenic". Taken together, this variant is classified as pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	BRCA2-related disorders Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046239.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: This frameshifting variant in exon 8 of 28 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function … (more) This frameshifting variant in exon 8 of 28 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported in individuals with breast and ovarian cancer (PMID: 22923021, 23767878, 28324225). This variant has also been reported as a compound heterozygous change in patients with Fanconi anemia (PMID: 16825431). Loss-of-function variation in BRCA2 is an established mechanism of disease (PMID: 20104584). The c.658_659del (p.Val220IlefsTer4) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (13/276414) and thus is presumed to be rare. Based on the available evidence, the c.658_659del (p.Val220IlefsTer4) variant is classified as Pathogenic. (less)
Pathogenic (Mar 02, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000296738.7 First in ClinVar: Jun 24, 2016 Last updated: Jan 06, 2024	Publications: PubMed (53): PubMed: 26295337 25066507 22923021 22798144 29446198 31112363 32098980 32875559 32438681 33478551 33471991 35220195 14670928 15689453 22535016 26026974 26064523 26681312 26689913 27153395 27741520 27831900 28724667 29753700 29790872 30093976 30122538 30630528 30720243 30787465 31263054 31396961 31411802 31447099 31589614 31825140 31948886 31957001 31980526 32318955 32341426 32467295 32719484 34008015 9667259 16825431 23767878 26657402 24504028 30287823 29492181 29339979 30350268 Comment: 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 … (more) 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 breast and/or ovarian cancer (PMIDs: 35220195 (2022), 33478551 (2021), 32438681 (2020), 32098980 (2020), 32341426 (2020), 32318955 (2020), 31980526 (2020), 31957001 (2020), 31411802 (2019), 31263054 (2019), 30350268 (2018), 30287823 (2018), 29492181 (2018)). Additionally, the variant has been reported in individuals with prostate cancer (PMIDs: 31948886 (2020), 32875559 (2020)), colorectal cancer (PMID: 26681312 (2015)), mesothelioma (PMID: 34008015 (2021), and esophageal squamous cell carcinoma (PMID: 31396961 (2020)). The variant has occurred with an additional pathogenic BRCA2 variant in children with Fanconi Anemia, Wilm's tumor, and/or medulloblastoma (PMIDs: 29753700 (2018), 26657402 (2016), 26064523 (2015), 16825431 (2007), 15689453 (2005), 14670928 (2004)). The frequency of this variant in the general population, 0.00013 (3/23770 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Mar 03, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003814404.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000073001.15 First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 28492532‚ 20104584‚ 9667259‚ 22923021‚ 23767878‚ 24504028‚ 26657402 Comment: This sequence change creates a premature translational stop signal (p.Val220Ilefs4) in the BRCA2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Val220Ilefs4) 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 (rs768580992, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 9667259, 22923021, 23767878, 24504028, 26657402). This variant is also known as 886delGT. ClinVar contains an entry for this variant (Variation ID: 9342). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 10, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV002049181.5 First in ClinVar: Jan 08, 2022 Last updated: Feb 20, 2024	Comment: The BRCA2 c.658_659delGT; p.Val220IlefsTer4 variant (rs80359604), also known as 886delGT, is reported in the literature in multiple individuals affected with hereditary breast and ovarian cancer … (more) The BRCA2 c.658_659delGT; p.Val220IlefsTer4 variant (rs80359604), also known as 886delGT, is reported in the literature in multiple individuals affected with hereditary breast and ovarian cancer syndrome (Cunningham 2014, de Juan 2015, Frank 1998, Heramb 2018), and in patients with Fanconi anemia when found in-trans with another pathogenic variant (Hirsch 2004, Svojgr 2016). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 9342), and is found in the African/African American population with an allele frequency of 0.013% (3/23,770 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 2 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Val220IlefsTer4 variant is considered to be pathogenic. References: Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014 4:4026. PMID: 24504028. 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 14(4):505-13. PMID: 26026974. Frank T et al. Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol. 1998 16(7):2417-25. PMID: 9667259. Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. PMID: 29339979. Hirsch B et al. Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. Blood. 2004 103(7):2554-9. PMID: 14670928. Svojgr K et al. Fanconi anemia with biallelic FANCD1/BRCA2 mutations - Case report of a family with three affected children. Eur J Med Genet. 2016 59(3):152-7. PMID: 26657402. (less)
Pathogenic (Jan 08, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004846802.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (8) PubMed: 11897832‚ 22923021‚ 29446198‚ 32571290‚ 32824581‚ 33478551‚ 33670479‚ 34097676 Comment: The c.658_659delGT (p.Val220Ilefs4) variant in the BRCA2 gene is located on the exon 8 and is predicted to cause reading frame shift that introduces a … (more) The c.658_659delGT (p.Val220Ilefs4) variant in the BRCA2 gene is located on the exon 8 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Val220Ilefs4), resulting in an absent or disrupted protein product. Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 11897832). This c.658_659delGT variant was reported in more than 10 unrelated individuals with ovarian/breast cancer (PMID: 33478551, 34097676, 33670479, 32571290, 32824581, 22923021). It is one of the most frequently observed BRCA2 variants in North America and Lithuania, and more than 20 families were reported with the variant and disease (PMID: 29446198). This variant is reported in ClinVar as pathogenic (ID: 9342) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (13/276414). Therefore, the c.658_659delGT (p.Val220Ilefs4) variant of BRCA2 has been classified as pathogenic. (less) Number of individuals with the variant: 13
Pathogenic (Nov 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000605780.3 First in ClinVar: Aug 05, 2017 Last updated: Apr 20, 2024	Publications: PubMed (6) PubMed: 9667259‚ 14559878‚ 14670928‚ 15689453‚ 23767878‚ 25066507 Comment: The p.Val220IlefsX4 variant in BRCA2 has been identified in >50 individuals with BRCA2-associated cancers (Frank 1998 PMID:9667259, Berzina 2013 PMID:23767878, Breast Cancer Information Core (BIC) … (more) The p.Val220IlefsX4 variant in BRCA2 has been identified in >50 individuals with BRCA2-associated cancers (Frank 1998 PMID:9667259, Berzina 2013 PMID:23767878, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/) and in 3 compound heterozygous individuals with Fanconi anemia (Offit 2003 PMID:14559878, Hirsch 2004 PMID:14670928, Reid 2005 PMID:15689453). It has also been identified in 0.012% (5/41438) of African/African American chromosomes and in 0.003% (2/68004) of 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 220 and leads to a premature termination codon 4 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 hereditary breast and ovarian cancer (HBOC). Additionally, this variant was classified as pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 9342). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PVS1. (less)
Pathogenic (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005196833.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Nov 20, 2015)	criteria provided, single submitter (Shirts et al. (Genet Med 2016)) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 1 Affected status: yes Allele origin: germline	University of Washington Department of Laboratory Medicine, University of Washington Accession: SCV000266043.1 First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016	Observation 1: Number of individuals with the variant: 1 Clinical Features: bilateral breast cancer (present) Age: 50-59 years Observation 2: Number of individuals with the variant: 1 Clinical Features: breast cancer (present) Age: 50-59 years
Pathogenic (Nov 03, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Michigan Medical Genetics Laboratories, University of Michigan Accession: SCV000195951.1 First in ClinVar: Mar 29, 2015 Last updated: Mar 29, 2015	Tissue: Blood
Pathogenic (Apr 02, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 1 Affected status: yes Allele origin: germline	Department of Molecular Diagnostics, Institute of Oncology Ljubljana Accession: SCV001499761.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
Pathogenic (Oct 25, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000778635.2 First in ClinVar: Jun 23, 2018 Last updated: Jun 02, 2021	Publications: PubMed (3) PubMed: 23767878‚ 22923021‚ 9667259 Comment: PVS1, PM2, PP5 Number of individuals with the variant: 1
Pathogenic (Oct 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial prostate cancer Affected status: unknown Allele origin: inherited	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn Accession: SCV002103004.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Comment: Incidental finding in clinical exome sequencing. PVS1, PS4, PS5
Pathogenic (Oct 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: inherited	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn Accession: SCV002103002.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Comment: Incidental finding in clinical exome sequencing. PVS1, PS4, PS5
Pathogenic (Oct 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: inherited	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn Accession: SCV002103003.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Comment: Incidental finding in clinical exome sequencing. PVS1, PS4, PS5
Pathogenic (Oct 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Medulloblastoma Affected status: unknown Allele origin: inherited	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn Accession: SCV002103005.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Comment: Incidental finding in clinical exome sequencing. PVS1, PS4, PS5
Pathogenic (Oct 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wilms tumor 1 Affected status: unknown Allele origin: inherited	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn Accession: SCV002103006.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Comment: Incidental finding in clinical exome sequencing. PVS1, PS4, PS5
Pathogenic (Oct 06, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Department of Medical Genetics, Oslo University Hospital Accession: SCV000605688.3 First in ClinVar: Sep 28, 2017 Last updated: Dec 11, 2022	Number of individuals with the variant: 1
Pathogenic (Feb 04, 2015)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: literature only	Breast-ovarian cancer, familial 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000221117.2 First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022	Publications: PubMed (9) PubMed: 16912212‚ 17513806‚ 14647210‚ 16825431‚ 22009639‚ 24504028‚ 22535016‚ 23767878‚ 9667259
Pathogenic (Oct 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Medulloblastoma Familial prostate cancer Wilms tumor 1 Fanconi anemia complementation group D1 Breast-ovarian cancer, familial, susceptibility to, 2 Glioma susceptibility 3 Pancreatic cancer, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002812445.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Sep 19, 2022)	criteria provided, single submitter (ICSL CNVClassificationCriteria Aug2020) Method: clinical testing	Not provided Affected status: yes Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV003802786.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023	Publications: PubMed (6) PubMed: 23767878‚ 24504028‚ 27153395‚ 9667259‚ 26064523‚ 14670928 Comment: The BRCA2 c.658_659delGT (p.Val220IlefsTer4) variant results in the deletion of two nucleotides at position c.658-659, causing a shift in the protein reading frame that is … (more) The BRCA2 c.658_659delGT (p.Val220IlefsTer4) variant results in the deletion of two nucleotides at position c.658-659, causing a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. Across a selection of the available literature, the c.658_659delGT variant, also referred to as c.886delGT, has been identified in a heterozygous state in at least eight individuals with breast cancer and one individual with ovarian cancer (PMID: 9667259; PMID: 23767878; PMID: 24504028; PMID: 27153395). The variant has also been observed in a compound heterozygous state in at least seven individuals with Fanconi anemia (PMID: 14670928; PMID: 26064523). The highest frequency of this allele in the Genome Aggregation Database is 0.000126 in the African/African-American population. Based on the available evidence the c.658_659delGT (p.Val220IlefsTer4) variant is classified as pathogenic for hereditary breast and ovarian cancer. (less)
Pathogenic (Mar 16, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000108633.14 First in ClinVar: Dec 10, 2013 Last updated: Mar 04, 2023	Comment: Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed … (more) Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in the heterozygous state in individuals from hereditary breast and ovarian cancer families (Frank 1998, Jakubowska 2003, Machado 2007, Berzina 2013, Cunningham 2014, de Juan 2015); Observed in the compound heterozygous state with a second pathogenic BRCA2 variant in patients with Fanconi anemia (Alter 2007, Miele 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 886delGT; This variant is associated with the following publications: (PMID: 9667259, 14647210, 15689453, 27836010, 26681312, 30128899, 17513806, 23767878, 24504028, 26026974, 16825431, 26064523, 26779294, 24528374, 26843898, 22535016, 27376475, 27153395, 26657402, 27831900, 14559878, 14670928, 28724667, 28324225, 28166811, 22009639, 29339979, 29753700, 29492181, 30078507, 29310832, 30350268, 30630528, 30122538, 30720243, 29790872, 29575201, 30093976, 31411802, 31396961, 31263054, 31957001, 27741520, 29625052, 26689913, 32318955, 31447099, 31980526, 31948886, 34008015, 32467295, 31589614, 32341426, 31825140, 32719484, 30787465) (less)
Pathogenic (Dec 29, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001934294.2 First in ClinVar: Sep 25, 2021 Last updated: Feb 14, 2024	Comment: Criteria applied: PVS1,PM5_STR Clinical Features: Family history of cancer (present) Sex: female
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000292146.5 First in ClinVar: Jul 08, 2016 Last updated: Feb 14, 2024	Publications: PubMed (9) PubMed: 9667259‚ 16825431‚ 22923021‚ 23767878‚ 24504028‚ 27153395‚ 28324225‚ 28724667‚ 30287823 Comment: This variant deletes 2 nucleotides in exon 8 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known … (more) This variant deletes 2 nucleotides in exon 8 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 886delGT in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with breast and ovarian cancer (PMID: 9667259, 22923021, 23767878, 24504028, 27153395, 28324225, 28724667, 30287823). It has also been observed in compound heterozygous state with a pathogenic variant in two individuals affected with Fanconi anemia (PMID: 16825431). This variant has been identified in 13/276414 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. (less)
Pathogenic (Nov 17, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000186913.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (13) PubMed: 14559878‚ 14670928‚ 15689453‚ 26064523‚ 26657402‚ 26681312‚ 27153395‚ 27831900‚ 28324225‚ 28724667‚ 29339979‚ 29492181‚ 29753700 Comment: The c.658_659delGT pathogenic mutation, located in coding exon 7 of the BRCA2 gene, results from a deletion of 2 nucleotides at positions 658 to 659, … (more) The c.658_659delGT pathogenic mutation, located in coding exon 7 of the BRCA2 gene, results from a deletion of 2 nucleotides at positions 658 to 659, causing a translational frameshift with a predicted alternate stop codon (p.V220Ifs*4). This mutation has been described in numerous HBOC families (Frank TS et al. J. Clin. Oncol. 1998 Jul;16:2417-25; Berzina D et al. BMC Med. Genet. 2013;14:61; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). This mutation has also been observed in Fanconi anemia group D1 patients and was associated with brain tumors (medulloblastomas and glioblastomas) and Wilms tumor in these patients (Alter BP et al. J. Med. Genet. 2007 Jan;44:1-9; Miele E et al. Biomark Res. 2015;3:13). Of note, this alteration is also designated as 886delGT 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 classified as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised. (less)
Pathogenic (Feb 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV000540998.2 First in ClinVar: Apr 17, 2017 Last updated: Jun 17, 2024
Pathogenic (Dec 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247635.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: BRCA2: PVS1, PS3:Moderate, PS4:Supporting Number of individuals with the variant: 8
Pathogenic (Jan 04, 2014)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: not provided Allele origin: germline	Sharing Clinical Reports Project (SCRP) Accession: SCV000054244.6 First in ClinVar: Apr 04, 2013 Last updated: Jun 24, 2016
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733216.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (Jan 01, 2007)	no assertion criteria provided Method: literature only	FANCONI ANEMIA, COMPLEMENTATION GROUP D1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000030150.4 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (3) PubMed: 14670928‚ 15689453‚ 16825431 Comment on evidence: Fanconi Anemia In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 … (more) Fanconi Anemia In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 gene: a 2-bp deletion in exon 8 (886delGT), inherited from the father, and an 8447T-A transversion in exon 18, resulting in a leu2740-to-ter substitution (L2740X; 600185.0028), inherited from the mother. Wilms Tumor/Medulloblastoma/Glioblastoma In 2 brothers who developed Wilms tumor (WT1; 194070) and brain tumors, Reid et al. (2005) identified 2 truncating BRCA2 mutations: a paternally inherited 886delGT, predicted to truncate the protein at codon 223 before the 8 BRC repeats, and a maternally inherited 5873C-A transversion in exon 11, resulting in a ser1882-to-ter substitution (S1882X; 600185.0031) predicted to truncate the protein such that BRC7 and BRC8 would be missing. One boy developed a glioblastoma (GLM3; 613029); the other had recurrent medulloblastoma (MDB; 155255) as well as pre-B-cell acute lymphoblastic leukemia. Neither child had the typical clinical features of Fanconi anemia. No first- or second-degree relative had cancer when the family presented; however, after the boys died their mother developed breast cancer at age 45 as did a paternal aunt at age 48. Alter et al. (2007) included this mutation in an analysis of the clinical and molecular features associated with the BRCA2 mutations identified in FANCD1 patients. They noted that the 886delGT mutation is associated with brain tumors. They also concluded that small group of patients with biallelic mutations in BRCA2 is distinctive in the severity of the phenotype, with early onset and high rates of leukaemia and specific solid tumours. These features may comprise an extreme variant of Fanconi anemia. (less)
Pathogenic (Jan 01, 2007)	no assertion criteria provided Method: literature only	WILMS TUMOR Affected status: not provided Allele origin: germline	OMIM Accession: SCV000030151.4 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (3) PubMed: 14670928‚ 15689453‚ 16825431 Comment on evidence: Fanconi Anemia In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 … (more) Fanconi Anemia In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 gene: a 2-bp deletion in exon 8 (886delGT), inherited from the father, and an 8447T-A transversion in exon 18, resulting in a leu2740-to-ter substitution (L2740X; 600185.0028), inherited from the mother. Wilms Tumor/Medulloblastoma/Glioblastoma In 2 brothers who developed Wilms tumor (WT1; 194070) and brain tumors, Reid et al. (2005) identified 2 truncating BRCA2 mutations: a paternally inherited 886delGT, predicted to truncate the protein at codon 223 before the 8 BRC repeats, and a maternally inherited 5873C-A transversion in exon 11, resulting in a ser1882-to-ter substitution (S1882X; 600185.0031) predicted to truncate the protein such that BRC7 and BRC8 would be missing. One boy developed a glioblastoma (GLM3; 613029); the other had recurrent medulloblastoma (MDB; 155255) as well as pre-B-cell acute lymphoblastic leukemia. Neither child had the typical clinical features of Fanconi anemia. No first- or second-degree relative had cancer when the family presented; however, after the boys died their mother developed breast cancer at age 45 as did a paternal aunt at age 48. Alter et al. (2007) included this mutation in an analysis of the clinical and molecular features associated with the BRCA2 mutations identified in FANCD1 patients. They noted that the 886delGT mutation is associated with brain tumors. They also concluded that small group of patients with biallelic mutations in BRCA2 is distinctive in the severity of the phenotype, with early onset and high rates of leukaemia and specific solid tumours. These features may comprise an extreme variant of Fanconi anemia. (less)
Pathogenic (Jan 01, 2007)	no assertion criteria provided Method: literature only	MEDULLOBLASTOMA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000030153.4 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (3) PubMed: 14670928‚ 15689453‚ 16825431 Comment on evidence: Fanconi Anemia In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 … (more) Fanconi Anemia In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 gene: a 2-bp deletion in exon 8 (886delGT), inherited from the father, and an 8447T-A transversion in exon 18, resulting in a leu2740-to-ter substitution (L2740X; 600185.0028), inherited from the mother. Wilms Tumor/Medulloblastoma/Glioblastoma In 2 brothers who developed Wilms tumor (WT1; 194070) and brain tumors, Reid et al. (2005) identified 2 truncating BRCA2 mutations: a paternally inherited 886delGT, predicted to truncate the protein at codon 223 before the 8 BRC repeats, and a maternally inherited 5873C-A transversion in exon 11, resulting in a ser1882-to-ter substitution (S1882X; 600185.0031) predicted to truncate the protein such that BRC7 and BRC8 would be missing. One boy developed a glioblastoma (GLM3; 613029); the other had recurrent medulloblastoma (MDB; 155255) as well as pre-B-cell acute lymphoblastic leukemia. Neither child had the typical clinical features of Fanconi anemia. No first- or second-degree relative had cancer when the family presented; however, after the boys died their mother developed breast cancer at age 45 as did a paternal aunt at age 48. Alter et al. (2007) included this mutation in an analysis of the clinical and molecular features associated with the BRCA2 mutations identified in FANCD1 patients. They noted that the 886delGT mutation is associated with brain tumors. They also concluded that small group of patients with biallelic mutations in BRCA2 is distinctive in the severity of the phenotype, with early onset and high rates of leukaemia and specific solid tumours. These features may comprise an extreme variant of Fanconi anemia. (less)
risk factor (Jan 01, 2007)	no assertion criteria provided Method: literature only	GLIOMA SUSCEPTIBILITY 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000030152.4 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (3) PubMed: 14670928‚ 15689453‚ 16825431 Comment on evidence: Fanconi Anemia In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 … (more) Fanconi Anemia In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 gene: a 2-bp deletion in exon 8 (886delGT), inherited from the father, and an 8447T-A transversion in exon 18, resulting in a leu2740-to-ter substitution (L2740X; 600185.0028), inherited from the mother. Wilms Tumor/Medulloblastoma/Glioblastoma In 2 brothers who developed Wilms tumor (WT1; 194070) and brain tumors, Reid et al. (2005) identified 2 truncating BRCA2 mutations: a paternally inherited 886delGT, predicted to truncate the protein at codon 223 before the 8 BRC repeats, and a maternally inherited 5873C-A transversion in exon 11, resulting in a ser1882-to-ter substitution (S1882X; 600185.0031) predicted to truncate the protein such that BRC7 and BRC8 would be missing. One boy developed a glioblastoma (GLM3; 613029); the other had recurrent medulloblastoma (MDB; 155255) as well as pre-B-cell acute lymphoblastic leukemia. Neither child had the typical clinical features of Fanconi anemia. No first- or second-degree relative had cancer when the family presented; however, after the boys died their mother developed breast cancer at age 45 as did a paternal aunt at age 48. Alter et al. (2007) included this mutation in an analysis of the clinical and molecular features associated with the BRCA2 mutations identified in FANCD1 patients. They noted that the 886delGT mutation is associated with brain tumors. They also concluded that small group of patients with biallelic mutations in BRCA2 is distinctive in the severity of the phenotype, with early onset and high rates of leukaemia and specific solid tumours. These features may comprise an extreme variant of Fanconi anemia. (less)
Pathogenic (Jun 25, 2024)	no assertion criteria provided Method: clinical testing	BRCA2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000805748.3 First in ClinVar: Jun 23, 2018 Last updated: Oct 08, 2024	Comment: The BRCA2 c.658_659delGT variant is predicted to result in a frameshift and premature protein termination (p.Val220Ilefs4). This variant is alternatively described as c.658delGT, c.886delGT or … (more) The BRCA2 c.658_659delGT variant is predicted to result in a frameshift and premature protein termination (p.Val220Ilefs4). This variant is alternatively described as c.658delGT, c.886delGT or c.886_887delGT. This variant has been observed in individuals with personal and family histories of breast and/or ovarian cancer (Novakovic et al. 2012. PubMed ID: 22923021; Berzina et al. 2013. PubMed ID: 23767878; Tung et al. 2016. PubMed ID: 26976419), Fanconi anemia (group D1), and other types of malignancies, including brain tumors (Offit et al. 2003. PubMed ID: 14559878; Reid et al. 2005. PubMed ID: 15689453; Alter et al. 2006, PubMed ID: 16825431). This variant, in combination with another variant in the same or a different gene, has also been reported in individuals with multiple malignancies including colorectal cancer (Heidemann et al. 2012. PubMed ID: 22535016; Degrolard-Courcet et al. 2014, PubMed ID: 24301060). This variant is reported in 0.013% of alleles in individuals of African descent in gnomAD. In ClinVar, it has been classified as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/9342). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (May 29, 2002)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: yes Allele origin: germline, unknown	Breast Cancer Information Core (BIC) (BRCA2) Accession: SCV000147427.2 First in ClinVar: Apr 01, 2014 Last updated: Mar 29, 2015	Observation 1: Number of individuals with the variant: 7 Observation 2: Number of individuals with the variant: 1 Geographic origin: Western European Observation 3: Number of individuals with the variant: 7 Ethnicity/Population group: Central/Eastern European Observation 4: Number of individuals with the variant: 3 Ethnicity/Population group: Latin American, Caribbean Observation 5: Number of individuals with the variant: 1 Ethnicity/Population group: Latin American, Caribbean, Hispanic Observation 6: Number of individuals with the variant: 17 Ethnicity/Population group: Western European Observation 7: Number of individuals with the variant: 1 Ethnicity/Population group: Latino
Pathogenic (Jan 31, 2014)	no assertion criteria provided Method: research	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000587560.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017
Pathogenic (Dec 04, 2016)	no assertion criteria provided Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000863725.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018
Pathogenic (Jun 11, 2019)	no assertion criteria provided Method: case-control, clinical testing	Breast and/or ovarian cancer Affected status: yes, no Allele origin: germline	CZECANCA consortium Accession: SCV001451877.1 First in ClinVar: Dec 24, 2020 Last updated: Dec 24, 2020	Publications: PubMed (1) PubMed: 32295079 Observation 1: Number of individuals with the variant: 1 Ethnicity/Population group: Slavic Geographic origin: Czech Republic Observation 2: Number of individuals with the variant: 6 Ethnicity/Population group: Slavic Geographic origin: Czech Republic
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Malignant tumor of breast Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001552307.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The BRCA2 p.Val220Ilefs4 variant was identified in 19 of 19400 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Bayraktar 2012, … (more) The BRCA2 p.Val220Ilefs4 variant was identified in 19 of 19400 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Bayraktar 2012, Berzina 2013, Frank 1998, Heidemann 2012, Janavicius 2014, Novakovic 2012). The variant was also identified in the case study in two siblings with Fanconi anemia with biallelic FANCD1/BRCA2 mutations (Svojgr 2016). The variant was also identified in dbSNP (ID: rs80359604) as â€šÃ„ÃºWith Pathogenic alleleâ€šÃ„Ã¹, ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and seventeen other submitters), LOVD 3.0 (58X as pathogenic), and in UMD-LSDB (30X as causal). This mutation was found at a high frequency in the Lithuanian population and could represent a Baltic founder mutation (Janavicius 2014).The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.658_659del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 220 and leads to a premature stop codon at position 223. 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 BRCA associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. (less)
Pathogenic (-)	no assertion criteria provided Method: literature only	Familial cancer of breast Affected status: yes Allele origin: germline	Center for Precision Medicine, Meizhou People's Hospital Accession: SCV002520927.1 First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022	Publications: PubMed (3) PubMed: 23767878‚ 22923021‚ 9667259
Pathogenic (Aug 26, 2022)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	BRCAlab, Lund University Accession: SCV002588849.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Pathogenic (Jul 01, 2021)	no assertion criteria provided Method: research	Gastric cancer Affected status: unknown Allele origin: germline	Laboratory for Genotyping Development, RIKEN Accession: SCV002758326.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Publications: PubMed (1) PubMed: 36988593
Pathogenic (Feb 21, 2023)	no assertion criteria provided Method: clinical testing	Uterine corpus cancer Affected status: yes Allele origin: germline	CZECANCA consortium Accession: SCV003804356.1 First in ClinVar: Feb 25, 2023 Last updated: Feb 25, 2023	Number of individuals with the variant: 1 Ethnicity/Population group: Slavic Geographic origin: Czech Republic
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Comment:

Variant summary: The c.658_659delGT variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.755_758delACAG, p.Asp252fsX24; c.771_775delTCAAA, p.Asn257fsX17; c.778_779delGA, p.Glu260fsX15). The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.006% which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). The variant has been reported in numerous affected individuals in the literature, including 2 siblings affected with Fanconi anemia who also carried a second pathogenic BRCA2 variant (Svojgr_2016). Mutliple reputable clinical labs have classified the variant as "Pathogenic". Taken together, this variant is classified as pathogenic.

Comment:

This frameshifting variant in exon 8 of 28 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported in individuals with breast and ovarian cancer (PMID: 22923021, 23767878, 28324225). This variant has also been reported as a compound heterozygous change in patients with Fanconi anemia (PMID: 16825431). Loss-of-function variation in BRCA2 is an established mechanism of disease (PMID: 20104584). The c.658_659del (p.Val220IlefsTer4) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (13/276414) and thus is presumed to be rare. Based on the available evidence, the c.658_659del (p.Val220IlefsTer4) variant is classified as Pathogenic.

Comment:

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 breast and/or ovarian cancer (PMIDs: 35220195 (2022), 33478551 (2021), 32438681 (2020), 32098980 (2020), 32341426 (2020), 32318955 (2020), 31980526 (2020), 31957001 (2020), 31411802 (2019), 31263054 (2019), 30350268 (2018), 30287823 (2018), 29492181 (2018)). Additionally, the variant has been reported in individuals with prostate cancer (PMIDs: 31948886 (2020), 32875559 (2020)), colorectal cancer (PMID: 26681312 (2015)), mesothelioma (PMID: 34008015 (2021), and esophageal squamous cell carcinoma (PMID: 31396961 (2020)). The variant has occurred with an additional pathogenic BRCA2 variant in children with Fanconi Anemia, Wilm's tumor, and/or medulloblastoma (PMIDs: 29753700 (2018), 26657402 (2016), 26064523 (2015), 16825431 (2007), 15689453 (2005), 14670928 (2004)). The frequency of this variant in the general population, 0.00013 (3/23770 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Val220Ilefs*4) 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 (rs768580992, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 9667259, 22923021, 23767878, 24504028, 26657402). This variant is also known as 886delGT. ClinVar contains an entry for this variant (Variation ID: 9342). For these reasons, this variant has been classified as Pathogenic.

Comment:

The BRCA2 c.658_659delGT; p.Val220IlefsTer4 variant (rs80359604), also known as 886delGT, is reported in the literature in multiple individuals affected with hereditary breast and ovarian cancer syndrome (Cunningham 2014, de Juan 2015, Frank 1998, Heramb 2018), and in patients with Fanconi anemia when found in-trans with another pathogenic variant (Hirsch 2004, Svojgr 2016). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 9342), and is found in the African/African American population with an allele frequency of 0.013% (3/23,770 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 2 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Val220IlefsTer4 variant is considered to be pathogenic. References: Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014 4:4026. PMID: 24504028. 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 14(4):505-13. PMID: 26026974. Frank T et al. Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol. 1998 16(7):2417-25. PMID: 9667259. Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. PMID: 29339979. Hirsch B et al. Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. Blood. 2004 103(7):2554-9. PMID: 14670928. Svojgr K et al. Fanconi anemia with biallelic FANCD1/BRCA2 mutations - Case report of a family with three affected children. Eur J Med Genet. 2016 59(3):152-7. PMID: 26657402.

Comment:

The c.658_659delGT (p.Val220Ilefs*4) variant in the BRCA2 gene is located on the exon 8 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Val220Ilefs*4), resulting in an absent or disrupted protein product. Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 11897832). This c.658_659delGT variant was reported in more than 10 unrelated individuals with ovarian/breast cancer (PMID: 33478551, 34097676, 33670479, 32571290, 32824581, 22923021). It is one of the most frequently observed BRCA2 variants in North America and Lithuania, and more than 20 families were reported with the variant and disease (PMID: 29446198). This variant is reported in ClinVar as pathogenic (ID: 9342) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (13/276414). Therefore, the c.658_659delGT (p.Val220Ilefs*4) variant of BRCA2 has been classified as pathogenic.

Comment:

The p.Val220IlefsX4 variant in BRCA2 has been identified in >50 individuals with BRCA2-associated cancers (Frank 1998 PMID:9667259, Berzina 2013 PMID:23767878, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/) and in 3 compound heterozygous individuals with Fanconi anemia (Offit 2003 PMID:14559878, Hirsch 2004 PMID:14670928, Reid 2005 PMID:15689453). It has also been identified in 0.012% (5/41438) of African/African American chromosomes and in 0.003% (2/68004) of 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 220 and leads to a premature termination codon 4 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 hereditary breast and ovarian cancer (HBOC). Additionally, this variant was classified as pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 9342). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PVS1.

Comment:

The BRCA2 c.658_659delGT (p.Val220IlefsTer4) variant results in the deletion of two nucleotides at position c.658-659, causing a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. Across a selection of the available literature, the c.658_659delGT variant, also referred to as c.886delGT, has been identified in a heterozygous state in at least eight individuals with breast cancer and one individual with ovarian cancer (PMID: 9667259; PMID: 23767878; PMID: 24504028; PMID: 27153395). The variant has also been observed in a compound heterozygous state in at least seven individuals with Fanconi anemia (PMID: 14670928; PMID: 26064523). The highest frequency of this allele in the Genome Aggregation Database is 0.000126 in the African/African-American population. Based on the available evidence the c.658_659delGT (p.Val220IlefsTer4) variant is classified as pathogenic for hereditary breast and ovarian cancer.

Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in the heterozygous state in individuals from hereditary breast and ovarian cancer families (Frank 1998, Jakubowska 2003, Machado 2007, Berzina 2013, Cunningham 2014, de Juan 2015); Observed in the compound heterozygous state with a second pathogenic BRCA2 variant in patients with Fanconi anemia (Alter 2007, Miele 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 886delGT; This variant is associated with the following publications: (PMID: 9667259, 14647210, 15689453, 27836010, 26681312, 30128899, 17513806, 23767878, 24504028, 26026974, 16825431, 26064523, 26779294, 24528374, 26843898, 22535016, 27376475, 27153395, 26657402, 27831900, 14559878, 14670928, 28724667, 28324225, 28166811, 22009639, 29339979, 29753700, 29492181, 30078507, 29310832, 30350268, 30630528, 30122538, 30720243, 29790872, 29575201, 30093976, 31411802, 31396961, 31263054, 31957001, 27741520, 29625052, 26689913, 32318955, 31447099, 31980526, 31948886, 34008015, 32467295, 31589614, 32341426, 31825140, 32719484, 30787465)

Comment:

This variant deletes 2 nucleotides in exon 8 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 886delGT in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with breast and ovarian cancer (PMID: 9667259, 22923021, 23767878, 24504028, 27153395, 28324225, 28724667, 30287823). It has also been observed in compound heterozygous state with a pathogenic variant in two individuals affected with Fanconi anemia (PMID: 16825431). This variant has been identified in 13/276414 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.

Comment:

The c.658_659delGT pathogenic mutation, located in coding exon 7 of the BRCA2 gene, results from a deletion of 2 nucleotides at positions 658 to 659, causing a translational frameshift with a predicted alternate stop codon (p.V220Ifs*4). This mutation has been described in numerous HBOC families (Frank TS et al. J. Clin. Oncol. 1998 Jul;16:2417-25; Berzina D et al. BMC Med. Genet. 2013;14:61; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). This mutation has also been observed in Fanconi anemia group D1 patients and was associated with brain tumors (medulloblastomas and glioblastomas) and Wilms tumor in these patients (Alter BP et al. J. Med. Genet. 2007 Jan;44:1-9; Miele E et al. Biomark Res. 2015;3:13). Of note, this alteration is also designated as 886delGT 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 classified as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.

Comment:

The BRCA2 c.658_659delGT variant is predicted to result in a frameshift and premature protein termination (p.Val220Ilefs*4). This variant is alternatively described as c.658delGT, c.886delGT or c.886_887delGT. This variant has been observed in individuals with personal and family histories of breast and/or ovarian cancer (Novakovic et al. 2012. PubMed ID: 22923021; Berzina et al. 2013. PubMed ID: 23767878; Tung et al. 2016. PubMed ID: 26976419), Fanconi anemia (group D1), and other types of malignancies, including brain tumors (Offit et al. 2003. PubMed ID: 14559878; Reid et al. 2005. PubMed ID: 15689453; Alter et al. 2006, PubMed ID: 16825431). This variant, in combination with another variant in the same or a different gene, has also been reported in individuals with multiple malignancies including colorectal cancer (Heidemann et al. 2012. PubMed ID: 22535016; Degrolard-Courcet et al. 2014, PubMed ID: 24301060). This variant is reported in 0.013% of alleles in individuals of African descent in gnomAD. In ClinVar, it has been classified as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/9342). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

The BRCA2 p.Val220Ilefs*4 variant was identified in 19 of 19400 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Bayraktar 2012, Berzina 2013, Frank 1998, Heidemann 2012, Janavicius 2014, Novakovic 2012). The variant was also identified in the case study in two siblings with Fanconi anemia with biallelic FANCD1/BRCA2 mutations (Svojgr 2016). The variant was also identified in dbSNP (ID: rs80359604) as â€šÃ„ÃºWith Pathogenic alleleâ€šÃ„Ã¹, ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and seventeen other submitters), LOVD 3.0 (58X as pathogenic), and in UMD-LSDB (30X as causal). This mutation was found at a high frequency in the Lithuanian population and could represent a Baltic founder mutation (Janavicius 2014).The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.658_659del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 220 and leads to a premature stop codon at position 223. 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 BRCA associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer.	Usui Y	The New England journal of medicine	2023	PMID: 36988593
Evaluation of hereditary/familial breast cancer patients with multigene targeted next generation sequencing panel and MLPA analysis in Turkey.	Bora E	Cancer genetics	2022	PMID: 35220195
[Germline and Somatic Mutations in Archived Breast Cancer Specimens of Different Subtypes].	Abramov IS	Molekuliarnaia biologiia	2021	PMID: 34097676
Novel LRRK2 mutations and other rare, non-BAP1-related candidate tumor predisposition gene variants in high-risk cancer families with mesothelioma and other tumors.	Cheung M	Human molecular genetics	2021	PMID: 34008015
Recurrent Mutations in BRCA1, BRCA2, RAD51C, PALB2 and CHEK2 in Polish Patients with Ovarian Cancer.	Łukomska A	Cancers	2021	PMID: 33670479
BRCA1 and BRCA2 mutations in ovarian cancer patients from Belarus: update.	Savanevich A	Hereditary cancer in clinical practice	2021	PMID: 33478551
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Prevalence of BRCA1/BRCA2 pathogenic variation in Chinese Han population.	Dong H	Journal of medical genetics	2021	PMID: 32467295
Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland.	Wokołorczyk D	International journal of cancer	2020	PMID: 32875559
Prevalence of Recurrent Mutations Predisposing to Breast Cancer in Early-Onset Breast Cancer Patients from Poland.	Rogoża-Janiszewska E	Cancers	2020	PMID: 32824581
Population genetic screening efficiently identifies carriers of autosomal dominant diseases.	Grzymski JJ	Nature medicine	2020	PMID: 32719484
Multiple primary tumors: a case report and review of the literature.	Zhao Z	BMC musculoskeletal disorders	2020	PMID: 32571290
Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome.	Santonocito C	Cancers	2020	PMID: 32438681
Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes.	De Talhouet S	Scientific reports	2020	PMID: 32341426
Evaluation of pathogenetic mutations in breast cancer predisposition genes in population-based studies conducted among Chinese women.	Zeng C	Breast cancer research and treatment	2020	PMID: 32318955
Oncologist-led BRCA 'mainstreaming' in the ovarian cancer clinic: A study of 255 patients and its impact on their management.	Rumford M	Scientific reports	2020	PMID: 32098980
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.	Hou YC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31980526
BRCA1 c.5470_5477del, a founder mutation in Chinese Han breast cancer patients.	Meng H	International journal of cancer	2020	PMID: 31957001
Rare Germline Pathogenic Mutations of DNA Repair Genes Are Most Strongly Associated with Grade Group 5 Prostate Cancer.	Wu Y	European urology oncology	2020	PMID: 31948886
Comprehensive profiling of BRCA1 and BRCA2 variants in breast and ovarian cancer in Chinese patients.	Gao X	Human mutation	2020	PMID: 31825140
BRCA2 loss-of-function germline mutations are associated with esophageal squamous cell carcinoma risk in Chinese.	Ko JM	International journal of cancer	2020	PMID: 31396961
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: [email protected]	American journal of human genetics	2019	PMID: 31447099
BRCA mutation frequency and clinical features of ovarian cancer patients: A report from a Chinese study group.	Bu H	The journal of obstetrics and gynaecology research	2019	PMID: 31411802
Frequency of Pathogenic Germline Variants in CDH1, BRCA2, CHEK2, PALB2, BRCA1, and TP53 in Sporadic Lobular Breast Cancer.	Petridis C	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology	2019	PMID: 31263054
BRCA1 and BRCA2 pathogenic sequence variants in women of African origin or ancestry.	Friebel TM	Human mutation	2019	PMID: 31112363
Toward automation of germline variant curation in clinical cancer genetics.	Ravichandran V	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30787465
High prevalence of cancer-associated TP53 variants in the gnomAD database: A word of caution concerning the use of variant filtering.	Soussi T	Human mutation	2019	PMID: 30720243
Population and breast cancer patients' analysis reveals the diversity of genomic variation of the BRCA genes in the Mexican population.	Fernández-Lopez JC	Human genomics	2019	PMID: 30630528
Prevalence and oncologic outcomes of BRCA 1/2 mutations in unselected triple-negative breast cancer patients in Korea.	Ryu JM	Breast cancer research and treatment	2019	PMID: 30350268
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.	Momozawa Y	Nature communications	2018	PMID: 30287823
Evaluation of Recipients of Positive and Negative Secondary Findings Evaluations in a Hybrid CLIA-Research Sequencing Pilot.	Sapp JC	American journal of human genetics	2018	PMID: 30122538
Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers.	Chan GHJ	Oncotarget	2018	PMID: 30093976
Genomic sequencing identifies secondary findings in a cohort of parent study participants.	Thompson ML	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 29790872
Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.	Waszak SM	The Lancet. Oncology	2018	PMID: 29753700
Frequency of BRCA1 and BRCA2 causative founder variants in ovarian cancer patients in South-East Poland.	Kluz T	Hereditary cancer in clinical practice	2018	PMID: 29492181
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.	Rebbeck TR	Human mutation	2018	PMID: 29446198
BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway.	Heramb C	Hereditary cancer in clinical practice	2018	PMID: 29339979
Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients.	Sun J	Clinical cancer research : an official journal of the American Association for Cancer Research	2017	PMID: 28724667
Spectrum of genetic variants of BRCA1 and BRCA2 in a German single center study.	Meisel C	Archives of gynecology and obstetrics	2017	PMID: 28324225
Aggregate penetrance of genomic variants for actionable disorders in European and African Americans.	Natarajan P	Science translational medicine	2016	PMID: 27831900
Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry.	Fernandes GC	Oncotarget	2016	PMID: 27741520
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.	Maxwell KN	American journal of human genetics	2016	PMID: 27153395
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.	Susswein LR	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26681312
Fanconi anemia with biallelic FANCD1/BRCA2 mutations - Case report of a family with three affected children.	Svojgr K	European journal of medical genetics	2016	PMID: 26657402
Patterns and functional implications of rare germline variants across 12 cancer types.	Lu C	Nature communications	2015	PMID: 26689913
Characterization of medulloblastoma in Fanconi Anemia: a novel mutation in the BRCA2 gene and SHH molecular subgroup.	Miele E	Biomarker research	2015	PMID: 26064523
BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study.	de Juan I	Familial cancer	2015	PMID: 26026974
Comprehensive BRCA1 and BRCA2 mutational profile in Lithuania.	Janavičius R	Cancer genetics	2014	PMID: 25066507
Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status.	Cunningham JM	Scientific reports	2014	PMID: 24504028
Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer.	Tea MK	Maturitas	2014	PMID: 24156927
BRCA1/2 mutation screening in high-risk breast/ovarian cancer families and sporadic cancer patient surveilling for hidden high-risk families.	Berzina D	BMC medical genetics	2013	PMID: 23767878
Novel BRCA1 and BRCA2 pathogenic mutations in Slovene hereditary breast and ovarian cancer families.	Novaković S	International journal of oncology	2012	PMID: 22923021
Characteristics and spectrum of BRCA1 and BRCA2 mutations in 3,922 Korean patients with breast and ovarian cancer.	Kim H	Breast cancer research and treatment	2012	PMID: 22798144
Double heterozygosity for mutations in BRCA1 and BRCA2 in German breast cancer patients: implications on test strategies and clinical management.	Heidemann S	Breast cancer research and treatment	2012	PMID: 22535016
Predictive factors for BRCA1/BRCA2 mutations in women with ductal carcinoma in situ.	Bayraktar S	Cancer	2012	PMID: 22009639
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.	Borg A	Human mutation	2010	PMID: 20104584
The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families.	Palma MD	Cancer research	2008	PMID: 18703817
BRCA1 and BRCA2 mutations in Danish families with hereditary breast and/or ovarian cancer.	Thomassen M	Acta oncologica (Stockholm, Sweden)	2008	PMID: 18465347
Screening for a BRCA2 rearrangement in high-risk breast/ovarian cancer families: evidence for a founder effect and analysis of the associated phenotypes.	Machado PM	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2007	PMID: 17513806
Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2.	Alter BP	Journal of medical genetics	2007	PMID: 16825431
Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years.	Malone KE	Cancer research	2006	PMID: 16912212
Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour.	Reid S	Journal of medical genetics	2005	PMID: 15689453
Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood.	Hirsch B	Blood	2004	PMID: 14670928
A high frequency of BRCA2 gene mutations in Polish families with ovarian and stomach cancer.	Jakubowska A	European journal of human genetics : EJHG	2003	PMID: 14647210
Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia.	Offit K	Journal of the National Cancer Institute	2003	PMID: 14559878
BRCA2 gene mutations in families with aggregations of breast and stomach cancers.	Jakubowska A	British journal of cancer	2002	PMID: 12373604
Contribution of BRCA2 germline mutations to hereditary breast/ovarian cancer in Germany.	Hamann U	Journal of medical genetics	2002	PMID: 11897832
Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk.	Frank TS	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	1998	PMID: 9667259
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Text-mined citations for rs80359604 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.658_659del (p.Val220fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80359604 ...