VCV000051578.59 - ClinVar

NM_000059.4(BRCA2):c.3975_3978dup (p.Ala1327fs)

Germline

Top reviewed classifications are shown here.

Submission summary:

28 submissions

26 submitters

8 conditions

Reviewed by expert panel

Pathogenic

Sep 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.3975_3978dup (p.Ala1327fs)

Variation ID: 51578 Accession: VCV000051578.59

Type and length

Duplication, 4 bp

Location

Cytogenetic: 13q13.1 13: 32338329-32338330 (GRCh38) [ NCBI UCSC ] 13: 32912466-32912467 (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	May 10, 2016	Oct 13, 2024	Sep 8, 2016

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.3975_3978dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Ala1327fs	frameshift
NM_000059.3:c.3975_3978dupTGCT
NC_000013.11:g.32338330_32338333dup
NC_000013.10:g.32912467_32912470dup
NG_012772.3:g.27851_27854dup
LRG_293:g.27851_27854dup

... more HGVS ... less HGVS

Protein change

A1327fs

Other names

Canonical SPDI

NC_000013.11:32338329:TGCT:TGCTTGCT

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.

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA019317 dbSNP: rs397515636 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	18969	19128

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.
Hereditary breast ovarian cancer syndrome	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 19, 2024	RCV000044327.26
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 29, 2023	RCV000129632.21
Breast-ovarian cancer, familial, susceptibility to, 2	Pathogenic (11)	reviewed by expert panel	Sep 8, 2016	RCV000210997.27
Familial cancer of breast	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 18, 2023	RCV000238801.15
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jun 7, 2023	RCV000486384.21
Breast-ovarian cancer, familial, susceptibility to, 1	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 24, 2024	RCV001310147.10
Breast carcinoma	Pathogenic (1)	criteria provided, single submitter	Oct 5, 2022	RCV002294004.8
Malignant tumor of prostate	Pathogenic (1)	criteria provided, single submitter	Sep 28, 2021	RCV002288544.9

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 (Sep 08, 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: SCV000300692.2 First in ClinVar: Sep 24, 2016 Last updated: Sep 24, 2016	Comment: Variant allele predicted to encode a truncated non-functional protein.
Pathogenic (Jul 27, 2020)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary breast and ovarian cancer syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000694733.2 First in ClinVar: Dec 26, 2017 Last updated: Aug 10, 2020	Publications: PubMed (12) PubMed: 20104584‚ 18824701‚ 21232165‚ 21324516‚ 23397983‚ 22923021‚ 17997147‚ 17148771‚ 10978364‚ 16168118‚ 25366421‚ 29446198 Comment: Variant summary: BRCA2 c.3975_3978dupTGCT (p.Ala1327CysfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: BRCA2 c.3975_3978dupTGCT (p.Ala1327CysfsX4) 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 was absent in 229858 control chromosomes (gnomAD). c.3975_3978dupTGCT has been reported in the literature in several individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (e.g. Plaschke_2000, Pohlreich_2005, Brozek_2007, Spearman_2008, Borg_2010, Zhang_2011, Novakovic_2012, Krajc_2014, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Sep 28, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial prostate cancer Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580405.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PM2_SUP, PP4	Number of individuals with the variant: 1 Sex: male
Pathogenic (Jun 07, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000566285.8 First in ClinVar: Apr 27, 2017 Last updated: Jun 17, 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 individuals with a personal or family history consistent with pathogenic variants in this gene (Plaschke et al., 2000; Lubinski et al., 2004; Pohlreich et al., 2005; Borg et al., 2010; Stegel et al., 2011; Zhang et al., 2011; Novakovic et al., 2012; Karami et al., 2013; Janavicius et al., 2014; Krajc et al., 2014; Ratajska et al., 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4203_4206dupTGCT, 3978insTGCT, and 4206insTGCT; This variant is associated with the following publications: (PMID: 26689913, 31447099, 20104584, 25066507, 29907814, 31159747, 29922827, 30040829, 16168118, 10978364, 21324516, 21232165, 15131399, 26315209, 24312913, 28008555, 22923021, 25366421, 29101607, 27989354, 29161300, 30720243, 29945567, 29625052, 33891299, 35382848, 35409996, 23397983) (less)
Pathogenic (Apr 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004210346.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Mar 13, 2020)	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: SCV000296573.3 First in ClinVar: May 10, 2016 Last updated: Jan 06, 2024	Publications: PubMed (8) PubMed: 26295337‚ 28008555‚ 29161300‚ 27989354‚ 29907814‚ 25366421‚ 10978364‚ 1 Comment: This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in multiple individuals with breast, ovarian, male breast … (more) This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in multiple individuals with breast, ovarian, male breast and prostate cancers in the published literature (PMID: 29907814 (2018), 27989354 (2017), 29161300 (2017), 28008555 (2017), 25366421 (2015), 10978364 (2000)). Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Jan 19, 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: SCV000072340.13 First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024	Publications: PubMed (7) PubMed: 28492532‚ 20104584‚ 10978364‚ 16168118‚ 22923021‚ 25066507‚ 25366421 Comment: This sequence change creates a premature translational stop signal (p.Ala1327Cysfs4) 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.Ala1327Cysfs4) 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 (rs764689249, gnomAD 0.001%). This premature translational stop signal has been observed in individual(s) with breast cancer and breast and ovarian cancer (PMID: 10978364, 16168118, 20104584, 22923021, 25066507, 25366421). This variant is also known as 4206insTGCT. ClinVar contains an entry for this variant (Variation ID: 51578). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jul 20, 2023)	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: SCV004848650.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (12) PubMed: 10978364‚ 29625052‚ 30720243‚ 25366421‚ 29945567‚ 29161300‚ 31159747‚ 26689913‚ 27989354‚ 29907814‚ 31447099‚ 33891299 Comment: The p.Ala1327CysfsX4 variant in BRCA2 has been reported in >10 individuals with BRCA2-associated cancers, including 7 males (2 prostate; 5 breast cancer; Plaschke 2000 PMID: … (more) The p.Ala1327CysfsX4 variant in BRCA2 has been reported in >10 individuals with BRCA2-associated cancers, including 7 males (2 prostate; 5 breast cancer; Plaschke 2000 PMID: 10978364, Lu 2015 PMID: 26689913, Ratajska 2015 PMID: 25366421, Alemar 2017 PMID: 29161300, Na 2017 PMID: 27989354, Huang 2018 PMID: 29625052, Palmero 2018 PMID: 29907814, Young 2018 PMID: 29945567, Tsaousis 2019 PMID: 31159747, Strojnik 2021 PMID: 33891299). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1327 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 (BRCA2). Additionally, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 51578). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Moderate. (less)
Pathogenic (Dec 03, 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: SCV000184425.9 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (11) PubMed: 25366421‚ 27989354‚ 29446198‚ 29625052‚ 29907814‚ 29945567‚ 30613824‚ 31159747‚ 32321997‚ 33891299‚ 34445631 Comment: The c.3975_3978dupTGCT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of TGCT at nucleotide position 3975, causing a … (more) The c.3975_3978dupTGCT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of TGCT at nucleotide position 3975, causing a translational frameshift with a predicted alternate stop codon (p.A1327Cfs*4). This mutation has been reported in multiple breast, ovarian, and prostate cancer patients in the literature (e.g. Plaschke J et al. J. Med. Genet. 2000 Sep;37:E17; Pohlreich P et al. Breast Cancer Res. 2005 Jul;7:R728-36; Risch HA et al. J. Natl. Cancer Inst. 2006 Dec;98:1694-706; Ratajska M et al. J. Appl. Genet. 2015 May;56:193-8; Na R et al. Eur. Urol. 2017 05;71(5):740-747; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620), including male breast cancer patients (e.g. Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586; Strojnik K et al. Breast Cancer Res Treat, 2021 Aug;188:811-820). Of note, this mutation is also designated as 4206ins4 and 4203_4206dupTGCT 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. (less)
Pathogenic (Apr 21, 2016)	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: SCV000267763.1 First in ClinVar: May 10, 2016 Last updated: May 10, 2016	Tissue: Blood
Pathogenic (Apr 03, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV000839906.1 First in ClinVar: Nov 05, 2016 Last updated: Nov 05, 2016	Comment: This c.3975_3978dup (p.Ala1327Cysfs4) has previously been reported in at least two patients from two cohorts of 134 and 40 patients respectively [PMID 25366421, 10978364, reported … (more) This c.3975_3978dup (p.Ala1327Cysfs4) has previously been reported in at least two patients from two cohorts of 134 and 40 patients respectively [PMID 25366421, 10978364, reported as 4206insTGCT in the latter]. The c.3975_3978dup (p.Ala1327Cysfs*4) variant has been observed in one European (Non Finnish) individual at the heterozygous state in the ExAC database (http://exac.broadinstitute.org/variant/13-32912466-C-CTGCT). This 4 bp duplication is located in exon 11, and leads to the creation of a frameshift and a premature stop codon at amino acid position 1330 of the BRCA2 protein. It is thus classified as pathogenic. This variant is also considered medically actionable [ACMG59, PMID 27854360]. (less)
Pathogenic (Jan 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary Breast Carcinoma Affected status: yes Allele origin: germline	GeneKor MSA Accession: SCV000296821.4 First in ClinVar: Aug 01, 2016 Last updated: May 04, 2020	Comment: This sequence change is a duplication of 4 nucleotides in exon 11 of BRCA2 mRNA (c3975_3978dupTGCT), causing a frameshift after codon 1327 and the creation … (more) This sequence change is a duplication of 4 nucleotides in exon 11 of BRCA2 mRNA (c3975_3978dupTGCT), causing a frameshift after codon 1327 and the creation of a premature translation stop signal 4 amino acid residues later (p.Ala1327Cysfs*4). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This particular variant has been reported in international bibliography in breast and ovarian cancer patients (PMID: 25366421; PMID: 10978364 The mutation database ClinVar contains an entry for this variant (Variation ID: 51578). This variant is also known as 4206insTGCT in the literature using alternative nomenclature. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: no Allele origin: germline	Institute of Genomics, University of Tartu Accession: SCV001430700.1 First in ClinVar: Aug 24, 2020 Last updated: Aug 24, 2020	Number of individuals with the variant: 1
Pathogenic (Oct 10, 2014)	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: SCV001450246.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 6
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: SCV001499725.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
Pathogenic (Dec 02, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001428535.2 First in ClinVar: Aug 17, 2020 Last updated: Sep 25, 2021
Pathogenic (Oct 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast carcinoma Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002587078.1 First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022	Comment: _x000D_ Criteria applied: PVS1, PS4, PM2_SUP
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: SCV000326951.4 First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022
Pathogenic (Dec 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: no Allele origin: germline	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368695.4 First in ClinVar: Jul 06, 2020 Last updated: Feb 25, 2023	Comment: PVS1, PS4_STR PM2_SUP
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002010373.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Pathogenic (Dec 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003812497.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Nov 29, 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: SCV000683594.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (22) PubMed: 10978364‚ 16168118‚ 17148771‚ 17997147‚ 18824701‚ 20104584‚ 21232165‚ 21324516‚ 22923021‚ 23397983‚ 25066507‚ 25330149‚ 25366421‚ 28008555‚ 29161300‚ 29446198‚ 29907814‚ 30441849‚ 31409081‚ 33471991‚ 33891299‚ 34949660 Comment: This variant inserts 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known … (more) This variant inserts 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4206ins4 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 20 individuals affected with breast cancer, including 7 male individuals, and 5 individuals affected with ovarian cancer (PMID: 10978364, 16168118, 17148771, 17997147, 18824701, 20104584, 21324516, 25066507, 25330149, 25366421, 28008555, 29161300, 30441849, 33471991; Leiden Open Variation Database DB-ID BRCA2_002096, 33891299, 34949660). This variant has been reported in several hereditary breast and ovarian cancer families (PMID: 21232165, 22923021, 23397983, 29907814, 31409081) and has been identified in 10 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 1/225036 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 (Jan 22, 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: SCV004845252.1 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 (20) PubMed: 10978364‚ 16168118‚ 17148771‚ 17997147‚ 18824701‚ 20104584‚ 21232165‚ 21324516‚ 22923021‚ 23397983‚ 25066507‚ 25330149‚ 25366421‚ 28008555‚ 29161300‚ 29446198‚ 29907814‚ 30441849‚ 31409081‚ 33471991 Comment: This variant inserts 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known … (more) This variant inserts 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4206ins4 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 20 individuals affected with breast cancer, including 7 male individuals, and 5 individuals affected with ovarian cancer (PMID: 10978364, 16168118, 17148771, 17997147, 18824701, 20104584, 21324516, 25066507, 25330149, 25366421, 28008555, 29161300, 30441849, 33471991; Leiden Open Variation Database DB-ID BRCA2_002096, 33891299, 34949660). This variant has been reported in several hereditary breast and ovarian cancer families (PMID: 21232165, 22923021, 23397983, 29907814, 31409081) and has been identified in 10 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 1/225036 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) Number of individuals with the variant: 2
Pathogenic (Jun 24, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV005368512.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1,PS4,PM5_STR,PM2_SUP Clinical Features: Breast carcinoma (present) Sex: female
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: SCV000587692.1 First in ClinVar: Aug 07, 2017 Last updated: Aug 07, 2017
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 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: SCV001551160.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The BRCA2 p.Ala1327Cysfs4 variant was identified in 12 of 3586 proband chromosomes (frequency: 0.003) from European (Slovenian, Czech and Polish) individuals or families with breast … (more) The BRCA2 p.Ala1327Cysfs4 variant was identified in 12 of 3586 proband chromosomes (frequency: 0.003) from European (Slovenian, Czech and Polish) individuals or families with breast and ovarian cancer and male individuals with breast cancer; and was not identified in 80 control chromosomes from healthy individuals (Pohlreich 2005, Stegel 2011, Pritzaff 2016, Novakovic 2012, Ratajska 2015). The variant was also identified in dbSNP (ID: rs764689249) as â€šÃ„ÃºNAâ€šÃ„Ã¹, ClinVar (classified pathogenic, reviewed by an expert panel (2019); submitters: ENIGMA, Invitae, Ambry Genetics, GeneDx, and 8 other laboratories), and LOVD 3.0 (1x). The variant was not identified in UMD-LSDB (unavailable) or in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3975_3978dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1327 and leads to a premature stop codon at position 1331. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. (less)
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: SCV002588870.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Pathogenic (-)	no assertion criteria provided Method: research	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Medical Genetics, Medical University Pleven Accession: SCV004100895.1 First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023
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Comment:

Variant summary: BRCA2 c.3975_3978dupTGCT (p.Ala1327CysfsX4) 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 was absent in 229858 control chromosomes (gnomAD). c.3975_3978dupTGCT has been reported in the literature in several individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (e.g. Plaschke_2000, Pohlreich_2005, Brozek_2007, Spearman_2008, Borg_2010, Zhang_2011, Novakovic_2012, Krajc_2014, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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 individuals with a personal or family history consistent with pathogenic variants in this gene (Plaschke et al., 2000; Lubinski et al., 2004; Pohlreich et al., 2005; Borg et al., 2010; Stegel et al., 2011; Zhang et al., 2011; Novakovic et al., 2012; Karami et al., 2013; Janavicius et al., 2014; Krajc et al., 2014; Ratajska et al., 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4203_4206dupTGCT, 3978insTGCT, and 4206insTGCT; This variant is associated with the following publications: (PMID: 26689913, 31447099, 20104584, 25066507, 29907814, 31159747, 29922827, 30040829, 16168118, 10978364, 21324516, 21232165, 15131399, 26315209, 24312913, 28008555, 22923021, 25366421, 29101607, 27989354, 29161300, 30720243, 29945567, 29625052, 33891299, 35382848, 35409996, 23397983)

Comment:

This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in multiple individuals with breast, ovarian, male breast and prostate cancers in the published literature (PMID: 29907814 (2018), 27989354 (2017), 29161300 (2017), 28008555 (2017), 25366421 (2015), 10978364 (2000)). Based on the available information, this variant is classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Ala1327Cysfs*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 (rs764689249, gnomAD 0.001%). This premature translational stop signal has been observed in individual(s) with breast cancer and breast and ovarian cancer (PMID: 10978364, 16168118, 20104584, 22923021, 25066507, 25366421). This variant is also known as 4206insTGCT. ClinVar contains an entry for this variant (Variation ID: 51578). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.Ala1327CysfsX4 variant in BRCA2 has been reported in >10 individuals with BRCA2-associated cancers, including 7 males (2 prostate; 5 breast cancer; Plaschke 2000 PMID: 10978364, Lu 2015 PMID: 26689913, Ratajska 2015 PMID: 25366421, Alemar 2017 PMID: 29161300, Na 2017 PMID: 27989354, Huang 2018 PMID: 29625052, Palmero 2018 PMID: 29907814, Young 2018 PMID: 29945567, Tsaousis 2019 PMID: 31159747, Strojnik 2021 PMID: 33891299). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1327 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 (BRCA2). Additionally, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 51578). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Moderate.

Comment:

The c.3975_3978dupTGCT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of TGCT at nucleotide position 3975, causing a translational frameshift with a predicted alternate stop codon (p.A1327Cfs*4). This mutation has been reported in multiple breast, ovarian, and prostate cancer patients in the literature (e.g. Plaschke J et al. J. Med. Genet. 2000 Sep;37:E17; Pohlreich P et al. Breast Cancer Res. 2005 Jul;7:R728-36; Risch HA et al. J. Natl. Cancer Inst. 2006 Dec;98:1694-706; Ratajska M et al. J. Appl. Genet. 2015 May;56:193-8; Na R et al. Eur. Urol. 2017 05;71(5):740-747; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620), including male breast cancer patients (e.g. Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586; Strojnik K et al. Breast Cancer Res Treat, 2021 Aug;188:811-820). Of note, this mutation is also designated as 4206ins4 and 4203_4206dupTGCT 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.

Comment:

This c.3975_3978dup (p.Ala1327Cysfs*4) has previously been reported in at least two patients from two cohorts of 134 and 40 patients respectively [PMID 25366421, 10978364, reported as 4206insTGCT in the latter]. The c.3975_3978dup (p.Ala1327Cysfs*4) variant has been observed in one European (Non Finnish) individual at the heterozygous state in the ExAC database (http://exac.broadinstitute.org/variant/13-32912466-C-CTGCT). This 4 bp duplication is located in exon 11, and leads to the creation of a frameshift and a premature stop codon at amino acid position 1330 of the BRCA2 protein. It is thus classified as pathogenic. This variant is also considered medically actionable [ACMG59, PMID 27854360].

Comment:

This sequence change is a duplication of 4 nucleotides in exon 11 of BRCA2 mRNA (c3975_3978dupTGCT), causing a frameshift after codon 1327 and the creation of a premature translation stop signal 4 amino acid residues later (p.Ala1327Cysfs*4). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This particular variant has been reported in international bibliography in breast and ovarian cancer patients (PMID: 25366421; PMID: 10978364 The mutation database ClinVar contains an entry for this variant (Variation ID: 51578). This variant is also known as 4206insTGCT in the literature using alternative nomenclature.

Comment:

This variant inserts 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4206ins4 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 20 individuals affected with breast cancer, including 7 male individuals, and 5 individuals affected with ovarian cancer (PMID: 10978364, 16168118, 17148771, 17997147, 18824701, 20104584, 21324516, 25066507, 25330149, 25366421, 28008555, 29161300, 30441849, 33471991; Leiden Open Variation Database DB-ID BRCA2_002096, 33891299, 34949660). This variant has been reported in several hereditary breast and ovarian cancer families (PMID: 21232165, 22923021, 23397983, 29907814, 31409081) and has been identified in 10 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 1/225036 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 BRCA2 p.Ala1327Cysfs*4 variant was identified in 12 of 3586 proband chromosomes (frequency: 0.003) from European (Slovenian, Czech and Polish) individuals or families with breast and ovarian cancer and male individuals with breast cancer; and was not identified in 80 control chromosomes from healthy individuals (Pohlreich 2005, Stegel 2011, Pritzaff 2016, Novakovic 2012, Ratajska 2015). The variant was also identified in dbSNP (ID: rs764689249) as â€šÃ„ÃºNAâ€šÃ„Ã¹, ClinVar (classified pathogenic, reviewed by an expert panel (2019); submitters: ENIGMA, Invitae, Ambry Genetics, GeneDx, and 8 other laboratories), and LOVD 3.0 (1x). The variant was not identified in UMD-LSDB (unavailable) or in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3975_3978dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1327 and leads to a premature stop codon at position 1331. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our 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
Revisiting the Implications of Positive Germline Testing Results Using Multi-gene Panels in Breast Cancer Patients.	Tsaousis GN	Cancer genomics & proteomics	2022	PMID: 34949660
Genetic Variants and Tumor Immune Microenvironment: Clues for Targeted Therapies in Inflammatory Breast Cancer (IBC).	Gong Y	International journal of molecular sciences	2021	PMID: 34445631
Genetic testing results in Slovenian male breast cancer cohort indicate the BRCA2 7806-2A > G founder variant could be associated with higher male breast cancer risk.	Strojnik K	Breast cancer research and treatment	2021	PMID: 33891299
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
Points to consider for reporting of germline variation in patients undergoing tumor testing: a statement of the American College of Medical Genetics and Genomics (ACMG).	Li MM	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32321997
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: agibbs@bcm.edu	American journal of human genetics	2019	PMID: 31447099
Twenty Years of BRCA1 and BRCA2 Molecular Analysis at MMCI - Current Developments for the Classification of Variants.	Machackova E	Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti	2019	PMID: 31409081
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.	Tsaousis GN	BMC cancer	2019	PMID: 31159747
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
BRCA2-Associated Prostate Cancer in a Patient With Spinal and Bulbar Muscular Atrophy.	Conteduca V	JCO precision oncology	2018	PMID: 30613824
Spectrum and Prevalence of Pathogenic Variants in Ovarian Cancer Susceptibility Genes in a Group of 333 Patients.	Koczkowska M	Cancers	2018	PMID: 30441849
Pancreatic cancer as a sentinel for hereditary cancer predisposition.	Young EL	BMC cancer	2018	PMID: 29945567
The germline mutational landscape of BRCA1 and BRCA2 in Brazil.	Palmero EI	Scientific reports	2018	PMID: 29907814
Pathogenic Germline Variants in 10,389 Adult Cancers.	Huang KL	Cell	2018	PMID: 29625052
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 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population?	Alemar B	PloS one	2017	PMID: 29161300
Male breast cancer in a multi-gene panel testing cohort: insights and unexpected results.	Pritzlaff M	Breast cancer research and treatment	2017	PMID: 28008555
Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death.	Na R	European urology	2017	PMID: 27989354
Patterns and functional implications of rare germline variants across 12 cancer types.	Lu C	Nature communications	2015	PMID: 26689913
Mutational analysis of BRCA1/2 in a group of 134 consecutive ovarian cancer patients. Novel and recurrent BRCA1/2 alterations detected by next generation sequencing.	Ratajska M	Journal of applied genetics	2015	PMID: 25366421
Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland.	Cybulski C	Clinical genetics	2015	PMID: 25330149
Comprehensive BRCA1 and BRCA2 mutational profile in Lithuania.	Janavičius R	Cancer genetics	2014	PMID: 25066507
Geographical distribution of Slovenian BRCA1/2 families according to family origin: implications for genetic screening.	Krajc M	Clinical genetics	2014	PMID: 23397983
Novel BRCA1 and BRCA2 pathogenic mutations in Slovene hereditary breast and ovarian cancer families.	Novaković S	International journal of oncology	2012	PMID: 22923021
Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer.	Zhang S	Gynecologic oncology	2011	PMID: 21324516
The occurrence of germline BRCA1 and BRCA2 sequence alterations in Slovenian population.	Stegel V	BMC medical genetics	2011	PMID: 21232165
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
Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance.	Spearman AD	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2008	PMID: 18824701
High frequency of BRCA1/2 germline mutations in consecutive ovarian cancer patients in Poland.	Brozek I	Gynecologic oncology	2008	PMID: 17997147
Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada.	Risch HA	Journal of the National Cancer Institute	2006	PMID: 17148771
High proportion of recurrent germline mutations in the BRCA1 gene in breast and ovarian cancer patients from the Prague area.	Pohlreich P	Breast cancer research : BCR	2005	PMID: 16168118
BRCA2 germline mutations among early onset breast cancer patients unselected for family history of the disease.	Plaschke J	Journal of medical genetics	2000	PMID: 10978364
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Text-mined citations for rs397515636 ...

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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.3975_3978dup (p.Ala1327fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397515636 ...