Variant allele predicted to encode a truncated non-functional protein.
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.3770_3771del (p.Glu1257fs)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Sep 2016 by
Evidence-based…
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007294.4(BRCA1):c.3770_3771del (p.Glu1257fs)
Variation ID: 37546 Accession: VCV000037546.69
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 17q21.31 17: 43091760-43091761 (GRCh38) [ NCBI UCSC ] 17: 41243777-41243778 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Sep 27, 2014 Oct 13, 2024 Sep 8, 2016 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- E1257fs, E1210fs, E1089fs, E1130fs, E1145fs, E1209fs, E1216fs, E1231fs, E1129fs, E1146fs, E1186fs, E1215fs, E1254fs, E1168fs, E1187fs, E1189fs, E961fs, E1169fs, E1190fs, E1230fs, E1256fs, E389fs
- Other names
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3888delGA
3889delAG
- Canonical SPDI
- NC_000017.11:43091759:CTCT:CT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
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| BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
13044 | 14850 | |
| LOC126862571 | - | - | - | GRCh38 | - | 1651 |
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. |
|---|---|---|---|---|
| Pathogenic (16) |
reviewed by expert panel
|
Sep 8, 2016 | RCV000031127.31 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 18, 2024 | RCV000048325.31 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 21, 2022 | RCV000131814.21 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 14, 2024 | RCV000235232.25 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 27, 2017 | RCV000677799.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Dec 1, 2018 | RCV000785411.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 4, 2021 | RCV001391223.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Aug 9, 2021 | RCV001554258.9 | |
|
BRCA1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Aug 26, 2024 | RCV004758609.1 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Sep 08, 2016)
|
reviewed by expert panel
Method: curation
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
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Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV000300013.2
First in ClinVar: Sep 24, 2016 Last updated: Sep 24, 2016 |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000076338.15
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu1257Glyfs*9) in the BRCA1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Glu1257Glyfs*9) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80357993, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 16683254, 17319787, 18627636, 23479189, 23683081). This variant is also known as 3890_3891delAG and 3889delAG. ClinVar contains an entry for this variant (Variation ID: 37546). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186869.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.3770_3771delAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 3770 to … (more)
The c.3770_3771delAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 3770 to 3771, causing a translational frameshift with a predicted alternate stop codon (p.E1257Gfs*9). This mutation has been reported in multiple breast and ovarian cancer families to date (Couch FJ et al. Hum. Mutat., 1996;8:8-18; Liede A et al. Am. J. Hum. Genet., 2002 Sep;71:595-606; Blay P et al. BMC Cancer, 2013 May;13:243; Rashid MU et al. BMC Cancer, 2016 08;16:673; Shi T et al. Int J Cancer, 2017 05;140:2051-2059; Cock-Rada AM et al. Fam Cancer, 2018 01;17:23-30; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Wen WX et al. J Med Genet, 2018 02;55:97-103; Rashid MU et al. Hered Cancer Clin Pract, 2019 Sep;17:27; Li JY et al. Int J Cancer, 2019 01;144:281-289; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; Deng M et al. Int J Cancer, 2019 09;145:1517-1528; Manchana T et al. World J Clin Oncol, 2019 Nov;10:358-368; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Meng H et al. Int J Cancer, 2020 06;146:3044-3052; Zeng C et al. Breast Cancer Res Treat, 2020 Jun;181:465-473; Dorling et al. N Engl J Med. 2021 02;384:428-439; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Feng Z et al. Ann Transl Med, 2021 Mar;9:364). Of note, this alteration is also designated as 3889delAG 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)
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Pathogenic
(Jul 01, 2015)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Department of Medical Genetics, Oslo University Hospital
Accession: SCV000564304.1
First in ClinVar: Apr 22, 2017 Last updated: Apr 22, 2017 |
Number of individuals with the variant: 3
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Pathogenic
(Jan 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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Genologica Medica
Additional submitter:
Servicio Andaluz de Salud, Hospital Universitario Virgen de la Victoria
Accession: SCV000577929.1
First in ClinVar: Apr 22, 2017 Last updated: Apr 22, 2017 |
Family history: yes
Ethnicity/Population group: Causasians
Geographic origin: Spain
Tissue: Blood
Secondary finding: no
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Pathogenic
(Nov 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000292519.11
First in ClinVar: Jul 24, 2016 Last updated: Dec 17, 2022 |
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 (Takahashi 1995, Liede 2002, Esteban Cardeosa 2010, Sakamoto 2016, Manchana 2019, Rashid 2019); 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 3889_3890delAG; This variant is associated with the following publications: (PMID: 25802882, 16758124, 11597388, 28127413, 28477318, 30078507, 29922827, 28888541, 29884136, 33858029, 7606717, 12181777, 20033483, 26439132, 30350268, 32318955, 8807330, 11106241, 24289553, 26026974, 26757417, 19941167, 23317271, 17076205, 23683081, 21559243, 20960228, 26911350, 27983536, 27393621, 27836010, 26848529, 27553291, 29215753, 28176296, 29093764, 28152038, 27062684, 28528518, 29339979, 29752822, 29907814, 29470806, 28724667, 28993434, 30675318, 30702160, 30720863, 30720243, 30972954, 23479189, 31815095, 31528241, 31957001, 31447099, 31589614, 32341426, 31825140, 32885271, 33151324, 31742824, 34645131, 35377489) (less)
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Pathogenic
(Jan 19, 2016)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000488193.2
First in ClinVar: Nov 05, 2016 Last updated: Dec 24, 2022 |
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Pathogenic
(Apr 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000296287.5
First in ClinVar: Oct 11, 2015 Last updated: Jan 06, 2024 |
Comment:
The BRCA1 c.3770_3771del (p.Glu1257Glyfs*9) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant … (more)
The BRCA1 c.3770_3771del (p.Glu1257Glyfs*9) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals with breast or ovarian cancer (PMID: 23479189 (2013), 30972954 (2019), 31957001 (2020); BRCA Exchange (http://brcaexchange.org/)). The frequency of this variant in the general population, 0.000087 (1/11484 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Dec 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003809158.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Feb 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004212772.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Mar 14, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198151.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Pathogenic
(Sep 21, 2015)
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criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744624.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Pathogenic
(Jun 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Ovarian cancer
Affected status: yes
Allele origin:
germline
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3DMed Clinical Laboratory Inc
Accession: SCV000803957.1
First in ClinVar: Aug 26, 2018 Last updated: Aug 26, 2018 |
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Pathogenic
(Oct 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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Familial breast-ovarian cancer 1
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434963.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The c.3770_3771delAG (p.Glu1257Glyfs*9) variant in the BRCA1 gene is predicted to introduce a premature translation termination codon, which is predicted to result in nonsense-mediated mRNA … (more)
The c.3770_3771delAG (p.Glu1257Glyfs*9) variant in the BRCA1 gene is predicted to introduce a premature translation termination codon, which is predicted to result in nonsense-mediated mRNA decay. This variant has been reported in multiple patients with hereditary breast and ovarian cancer (PMID 7606717, 16683254, 17319787, 18627636, 23479189, 27553291). This variant has an extremely low frequency in large databases of genetic variation in the general population. Therefore, the c.3770_3771delAG (p.Glu1257Glyfs*9) variant in the BRCA1 gene is classified as pathogenic. (less)
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Pathogenic
(Nov 27, 2014)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450255.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Nov 01, 2021)
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criteria provided, single submitter
Method: research
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Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
|
Genetics Program, Instituto Nacional de Cancer
Accession: SCV002515205.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
Geographic origin: Brazil
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Pathogenic
(Feb 01, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Arcensus
Accession: SCV002564555.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Oct 02, 2015)
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criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000325752.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(May 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV003923322.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
A known pathogenic mutation was detected in the BRCA1 gene(p.Glu1257fs).his sequence change creates a premature translational stop signal (p.Glu1257Glyfs*9) in the BRCA1 gene. It is … (more)
A known pathogenic mutation was detected in the BRCA1 gene(p.Glu1257fs).his sequence change creates a premature translational stop signal (p.Glu1257Glyfs*9) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80357993, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 16683254, 17319787, 18627636, 23479189, 23683081). This variant is also known as 3890_3891delAG and 3889delAG. ClinVar contains an entry for this variant (Variation ID: 37546). For these reasons, this variant has been classified as Pathogenic. This variant was confirmed by Sanger sequencing. (less)
Age: 30-39 years
Sex: female
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Pathogenic
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002760931.3
First in ClinVar: Dec 17, 2022 Last updated: Aug 18, 2023 |
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Pathogenic
(Sep 29, 2023)
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criteria provided, single submitter
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: SCV000918771.2
First in ClinVar: Jun 03, 2019 Last updated: Nov 04, 2023 |
Comment:
Variant summary: BRCA1 c.3770_3771delAG (p.Glu1257GlyfsX9) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is … (more)
Variant summary: BRCA1 c.3770_3771delAG (p.Glu1257GlyfsX9) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 8e-06 in 251226 control chromosomes (gnomAD). c.3770_3771delAG has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Takahashi_1995, Judkins_2005, Hansa_2012, Thirthagiri_2008, Sun_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 18627636, 7606717, 23317271, 28724667). 21 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 21, 2022)
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criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000683133.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as 3889delAG and 3888delGA in the literature according to the BIC nomenclature. This variant has been reported in over thirty individuals affected with breast and/or ovarian cancer (PMID: 18627636, 23479189, 23683081, 26026974, 26757417, 26824983, 27553291, 28176296, 28528518, 29339979). This variant has been identified in 2/251226 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(May 29, 2002)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline,
unknown
|
Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000144872.2
First in ClinVar: Apr 01, 2014 Last updated: Oct 11, 2015 |
Observation 1:
Number of individuals with the variant: 9
Observation 2:
Number of individuals with the variant: 1
Geographic origin: Western European
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: African
Observation 4:
Number of individuals with the variant: 3
Ethnicity/Population group: Caucasian
Geographic origin: Netherlands
Observation 5:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Geographic origin: Spain
Observation 6:
Number of individuals with the variant: 2
Ethnicity/Population group: Central/Eastern European
Observation 7:
Number of individuals with the variant: 1
Ethnicity/Population group: Central/Eastern European, Polish
Observation 8:
Number of individuals with the variant: 1
Ethnicity/Population group: Chinese
Geographic origin: Malaysia
Observation 9:
Number of individuals with the variant: 2
Ethnicity/Population group: Western European
Observation 10:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Asian
Observation 11:
Number of individuals with the variant: 1
Ethnicity/Population group: Han Chinese
Geographic origin: China
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
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: SCV001549686.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The BRCA1 p.Glu1257Glyfs*9 variant was identified in 27 of 18350 proband chromosomes (frequency: 0.0015) from individuals or families with breast or ovarian cancer (Blay 2013, … (more)
The BRCA1 p.Glu1257Glyfs*9 variant was identified in 27 of 18350 proband chromosomes (frequency: 0.0015) from individuals or families with breast or ovarian cancer (Blay 2013, Chen 2009, Cock-Rada 2018, de Juan Jimenez 2013, Heramb 2018, Hirotsu 2014, Konecny 2007, Thirthagiri 2008, van der Hout 2006). The variant was also identified in the following databases: dbSNP (ID: rs80357993) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and fourteen other submitters), COGR, LOVD 3.0 (28x), UMD-LSDB (25x causal), BIC Database (23x with clinical importance), ARUP Laboratories (definitely pathogenic), and in Zhejiang University database (2x). The variant was not identified in Cosmic or MutDB databases. 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.3770_3771del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1257 and leads to a premature stop codon at position 1265. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 01, 1999)
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no assertion criteria provided
Method: literature only
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BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000039545.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 28, 2015 |
Comment on evidence:
Tesoriero et al. (1999) identified a woman who developed high-grade breast cancer with axillary nodal metastases before the age of 40 years (604370). Her father … (more)
Tesoriero et al. (1999) identified a woman who developed high-grade breast cancer with axillary nodal metastases before the age of 40 years (604370). Her father developed prostate cancer during his early fifties. Her mother had no cancer. The patient was found to have a de novo 2-bp deletion (GA) at nucleotide 3888 in exon 11 of the BRCA1 gene (3888delGA), and a 1-bp deletion (T) at nucleotide 6174 in exon 11 of the BRCA2 gene (600185.0009), which had been inherited from the father. Studies of a heterozygous polymorphism indicated that the 3888delGA mutation of BRCA1 originated from the father. The authors noted that despite the large number of variants identified in the BRCA1 and BRCA2 (600185) genes, there appeared to be no earlier published report of a de novo mutation. (less)
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Pathogenic
(Dec 01, 2018)
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no assertion criteria provided
Method: research
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Ovarian neoplasm
Affected status: yes
Allele origin:
germline
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German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV000923983.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
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Pathogenic
(Mar 04, 2021)
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no assertion criteria provided
Method: clinical testing
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Carcinoma of pancreas
Affected status: yes
Allele origin:
germline
|
CZECANCA consortium
Accession: SCV001593139.1
First in ClinVar: May 16, 2021 Last updated: May 16, 2021 |
Number of individuals with the variant: 1
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
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Pathogenic
(Mar 23, 2012)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 1
Affected status: not provided
Allele origin:
germline
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Sharing Clinical Reports Project (SCRP)
Accession: SCV000053726.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014 |
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Pathogenic
(Jan 31, 2014)
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no assertion criteria provided
Method: research
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Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000587347.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733617.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Pathogenic
(Aug 09, 2021)
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no assertion criteria provided
Method: clinical testing
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Breast carcinoma
Affected status: yes
Allele origin:
germline
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Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
Accession: SCV001774865.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Age: 70-79 years
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Pathogenic
(May 03, 2021)
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no assertion criteria provided
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
|
Cancer Genomics Lab, PINUM Cancer Hospital
Accession: SCV004011748.1
First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023
Comment:
Breast Cancer <45 y; F/H Stomach and Thyroid Cancer
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Age: 30-39 years
Sex: female
Ethnicity/Population group: Pakistani
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Pathogenic
(Mar 02, 2020)
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no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
BRCAlab, Lund University
Accession: SCV004244026.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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Pathogenic
(May 24, 2021)
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no assertion criteria provided
Method: case-control
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)
Accession: SCV005061289.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
Secondary finding: no
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Pathogenic
(Aug 26, 2024)
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no assertion criteria provided
Method: clinical testing
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BRCA1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005348279.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The BRCA1 c.3770_3771delAG variant is predicted to result in a frameshift and premature protein termination (p.Glu1257Glyfs*9). This variant has been reported in patients with early … (more)
The BRCA1 c.3770_3771delAG variant is predicted to result in a frameshift and premature protein termination (p.Glu1257Glyfs*9). This variant has been reported in patients with early onset and familial breast and ovarian cancer (de Juan Jiménez et al. 2013. PubMed ID: 23479189; Gabaldó Barrios. 2017. PubMed ID: 28477318). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD and is reported in the ClinVar database as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37546/). Frameshift variants in BRCA1 are expected to be pathogenic. We interpret this variant as pathogenic. (less)
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Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Glu1257Glyfs*9) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80357993, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 16683254, 17319787, 18627636, 23479189, 23683081). This variant is also known as 3890_3891delAG and 3889delAG. ClinVar contains an entry for this variant (Variation ID: 37546). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.3770_3771delAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 3770 to 3771, causing a translational frameshift with a predicted alternate stop codon (p.E1257Gfs*9). This mutation has been reported in multiple breast and ovarian cancer families to date (Couch FJ et al. Hum. Mutat., 1996;8:8-18; Liede A et al. Am. J. Hum. Genet., 2002 Sep;71:595-606; Blay P et al. BMC Cancer, 2013 May;13:243; Rashid MU et al. BMC Cancer, 2016 08;16:673; Shi T et al. Int J Cancer, 2017 05;140:2051-2059; Cock-Rada AM et al. Fam Cancer, 2018 01;17:23-30; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Wen WX et al. J Med Genet, 2018 02;55:97-103; Rashid MU et al. Hered Cancer Clin Pract, 2019 Sep;17:27; Li JY et al. Int J Cancer, 2019 01;144:281-289; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; Deng M et al. Int J Cancer, 2019 09;145:1517-1528; Manchana T et al. World J Clin Oncol, 2019 Nov;10:358-368; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Meng H et al. Int J Cancer, 2020 06;146:3044-3052; Zeng C et al. Breast Cancer Res Treat, 2020 Jun;181:465-473; Dorling et al. N Engl J Med. 2021 02;384:428-439; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Feng Z et al. Ann Transl Med, 2021 Mar;9:364). Of note, this alteration is also designated as 3889delAG 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:
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 (Takahashi 1995, Liede 2002, Esteban Cardeosa 2010, Sakamoto 2016, Manchana 2019, Rashid 2019); 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 3889_3890delAG; This variant is associated with the following publications: (PMID: 25802882, 16758124, 11597388, 28127413, 28477318, 30078507, 29922827, 28888541, 29884136, 33858029, 7606717, 12181777, 20033483, 26439132, 30350268, 32318955, 8807330, 11106241, 24289553, 26026974, 26757417, 19941167, 23317271, 17076205, 23683081, 21559243, 20960228, 26911350, 27983536, 27393621, 27836010, 26848529, 27553291, 29215753, 28176296, 29093764, 28152038, 27062684, 28528518, 29339979, 29752822, 29907814, 29470806, 28724667, 28993434, 30675318, 30702160, 30720863, 30720243, 30972954, 23479189, 31815095, 31528241, 31957001, 31447099, 31589614, 32341426, 31825140, 32885271, 33151324, 31742824, 34645131, 35377489)
Comment:
The BRCA1 c.3770_3771del (p.Glu1257Glyfs*9) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals with breast or ovarian cancer (PMID: 23479189 (2013), 30972954 (2019), 31957001 (2020); BRCA Exchange (http://brcaexchange.org/)). The frequency of this variant in the general population, 0.000087 (1/11484 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Comment:
The c.3770_3771delAG (p.Glu1257Glyfs*9) variant in the BRCA1 gene is predicted to introduce a premature translation termination codon, which is predicted to result in nonsense-mediated mRNA decay. This variant has been reported in multiple patients with hereditary breast and ovarian cancer (PMID 7606717, 16683254, 17319787, 18627636, 23479189, 27553291). This variant has an extremely low frequency in large databases of genetic variation in the general population. Therefore, the c.3770_3771delAG (p.Glu1257Glyfs*9) variant in the BRCA1 gene is classified as pathogenic.
Comment:
A known pathogenic mutation was detected in the BRCA1 gene(p.Glu1257fs).his sequence change creates a premature translational stop signal (p.Glu1257Glyfs*9) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80357993, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 16683254, 17319787, 18627636, 23479189, 23683081). This variant is also known as 3890_3891delAG and 3889delAG. ClinVar contains an entry for this variant (Variation ID: 37546). For these reasons, this variant has been classified as Pathogenic. This variant was confirmed by Sanger sequencing.
Comment:
Variant summary: BRCA1 c.3770_3771delAG (p.Glu1257GlyfsX9) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 8e-06 in 251226 control chromosomes (gnomAD). c.3770_3771delAG has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Takahashi_1995, Judkins_2005, Hansa_2012, Thirthagiri_2008, Sun_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 18627636, 7606717, 23317271, 28724667). 21 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant deletes 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as 3889delAG and 3888delGA in the literature according to the BIC nomenclature. This variant has been reported in over thirty individuals affected with breast and/or ovarian cancer (PMID: 18627636, 23479189, 23683081, 26026974, 26757417, 26824983, 27553291, 28176296, 28528518, 29339979). This variant has been identified in 2/251226 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The BRCA1 p.Glu1257Glyfs*9 variant was identified in 27 of 18350 proband chromosomes (frequency: 0.0015) from individuals or families with breast or ovarian cancer (Blay 2013, Chen 2009, Cock-Rada 2018, de Juan Jimenez 2013, Heramb 2018, Hirotsu 2014, Konecny 2007, Thirthagiri 2008, van der Hout 2006). The variant was also identified in the following databases: dbSNP (ID: rs80357993) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and fourteen other submitters), COGR, LOVD 3.0 (28x), UMD-LSDB (25x causal), BIC Database (23x with clinical importance), ARUP Laboratories (definitely pathogenic), and in Zhejiang University database (2x). The variant was not identified in Cosmic or MutDB databases. 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.3770_3771del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1257 and leads to a premature stop codon at position 1265. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
The BRCA1 c.3770_3771delAG variant is predicted to result in a frameshift and premature protein termination (p.Glu1257Glyfs*9). This variant has been reported in patients with early onset and familial breast and ovarian cancer (de Juan Jiménez et al. 2013. PubMed ID: 23479189; Gabaldó Barrios. 2017. PubMed ID: 28477318). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD and is reported in the ClinVar database as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37546/). Frameshift variants in BRCA1 are expected to be pathogenic. We interpret this variant 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:
Variant allele predicted to encode a truncated non-functional protein.
Comment:
This sequence change creates a premature translational stop signal (p.Glu1257Glyfs*9) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80357993, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 16683254, 17319787, 18627636, 23479189, 23683081). This variant is also known as 3890_3891delAG and 3889delAG. ClinVar contains an entry for this variant (Variation ID: 37546). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.3770_3771delAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 3770 to 3771, causing a translational frameshift with a predicted alternate stop codon (p.E1257Gfs*9). This mutation has been reported in multiple breast and ovarian cancer families to date (Couch FJ et al. Hum. Mutat., 1996;8:8-18; Liede A et al. Am. J. Hum. Genet., 2002 Sep;71:595-606; Blay P et al. BMC Cancer, 2013 May;13:243; Rashid MU et al. BMC Cancer, 2016 08;16:673; Shi T et al. Int J Cancer, 2017 05;140:2051-2059; Cock-Rada AM et al. Fam Cancer, 2018 01;17:23-30; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Wen WX et al. J Med Genet, 2018 02;55:97-103; Rashid MU et al. Hered Cancer Clin Pract, 2019 Sep;17:27; Li JY et al. Int J Cancer, 2019 01;144:281-289; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; Deng M et al. Int J Cancer, 2019 09;145:1517-1528; Manchana T et al. World J Clin Oncol, 2019 Nov;10:358-368; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Meng H et al. Int J Cancer, 2020 06;146:3044-3052; Zeng C et al. Breast Cancer Res Treat, 2020 Jun;181:465-473; Dorling et al. N Engl J Med. 2021 02;384:428-439; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Feng Z et al. Ann Transl Med, 2021 Mar;9:364). Of note, this alteration is also designated as 3889delAG 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:
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 (Takahashi 1995, Liede 2002, Esteban Cardeosa 2010, Sakamoto 2016, Manchana 2019, Rashid 2019); 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 3889_3890delAG; This variant is associated with the following publications: (PMID: 25802882, 16758124, 11597388, 28127413, 28477318, 30078507, 29922827, 28888541, 29884136, 33858029, 7606717, 12181777, 20033483, 26439132, 30350268, 32318955, 8807330, 11106241, 24289553, 26026974, 26757417, 19941167, 23317271, 17076205, 23683081, 21559243, 20960228, 26911350, 27983536, 27393621, 27836010, 26848529, 27553291, 29215753, 28176296, 29093764, 28152038, 27062684, 28528518, 29339979, 29752822, 29907814, 29470806, 28724667, 28993434, 30675318, 30702160, 30720863, 30720243, 30972954, 23479189, 31815095, 31528241, 31957001, 31447099, 31589614, 32341426, 31825140, 32885271, 33151324, 31742824, 34645131, 35377489)
Comment:
The BRCA1 c.3770_3771del (p.Glu1257Glyfs*9) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals with breast or ovarian cancer (PMID: 23479189 (2013), 30972954 (2019), 31957001 (2020); BRCA Exchange (http://brcaexchange.org/)). The frequency of this variant in the general population, 0.000087 (1/11484 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Comment:
The c.3770_3771delAG (p.Glu1257Glyfs*9) variant in the BRCA1 gene is predicted to introduce a premature translation termination codon, which is predicted to result in nonsense-mediated mRNA decay. This variant has been reported in multiple patients with hereditary breast and ovarian cancer (PMID 7606717, 16683254, 17319787, 18627636, 23479189, 27553291). This variant has an extremely low frequency in large databases of genetic variation in the general population. Therefore, the c.3770_3771delAG (p.Glu1257Glyfs*9) variant in the BRCA1 gene is classified as pathogenic.
Comment:
A known pathogenic mutation was detected in the BRCA1 gene(p.Glu1257fs).his sequence change creates a premature translational stop signal (p.Glu1257Glyfs*9) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80357993, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 16683254, 17319787, 18627636, 23479189, 23683081). This variant is also known as 3890_3891delAG and 3889delAG. ClinVar contains an entry for this variant (Variation ID: 37546). For these reasons, this variant has been classified as Pathogenic. This variant was confirmed by Sanger sequencing.
Comment:
Variant summary: BRCA1 c.3770_3771delAG (p.Glu1257GlyfsX9) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 8e-06 in 251226 control chromosomes (gnomAD). c.3770_3771delAG has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Takahashi_1995, Judkins_2005, Hansa_2012, Thirthagiri_2008, Sun_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 18627636, 7606717, 23317271, 28724667). 21 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant deletes 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as 3889delAG and 3888delGA in the literature according to the BIC nomenclature. This variant has been reported in over thirty individuals affected with breast and/or ovarian cancer (PMID: 18627636, 23479189, 23683081, 26026974, 26757417, 26824983, 27553291, 28176296, 28528518, 29339979). This variant has been identified in 2/251226 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The BRCA1 p.Glu1257Glyfs*9 variant was identified in 27 of 18350 proband chromosomes (frequency: 0.0015) from individuals or families with breast or ovarian cancer (Blay 2013, Chen 2009, Cock-Rada 2018, de Juan Jimenez 2013, Heramb 2018, Hirotsu 2014, Konecny 2007, Thirthagiri 2008, van der Hout 2006). The variant was also identified in the following databases: dbSNP (ID: rs80357993) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and fourteen other submitters), COGR, LOVD 3.0 (28x), UMD-LSDB (25x causal), BIC Database (23x with clinical importance), ARUP Laboratories (definitely pathogenic), and in Zhejiang University database (2x). The variant was not identified in Cosmic or MutDB databases. 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.3770_3771del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1257 and leads to a premature stop codon at position 1265. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
The BRCA1 c.3770_3771delAG variant is predicted to result in a frameshift and premature protein termination (p.Glu1257Glyfs*9). This variant has been reported in patients with early onset and familial breast and ovarian cancer (de Juan Jiménez et al. 2013. PubMed ID: 23479189; Gabaldó Barrios. 2017. PubMed ID: 28477318). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD and is reported in the ClinVar database as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37546/). Frameshift variants in BRCA1 are expected to be pathogenic. We interpret this variant as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Featuring BRCA1 and BRCA2 germline mutational landscape from Asturias (North Spain). | Pitiot AS | Clinical genetics | 2024 | PMID: 38922859 |
| Familial history and prevalence of BRCA1, BRCA2 and TP53 pathogenic variants in HBOC Brazilian patients from a public healthcare service. | Matta BP | Scientific reports | 2022 | PMID: 36329109 |
| Homologous recombination repair gene mutations show no survival benefits in Chinese high-grade serous ovarian cancer patients. | Feng Z | Annals of translational medicine | 2021 | PMID: 33842585 |
| 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 |
| Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
| 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 |
| BRCA1 c.5470_5477del, a founder mutation in Chinese Han breast cancer patients. | Meng H | International journal of cancer | 2020 | PMID: 31957001 |
| Prevalence of hereditary breast and ovarian cancer (HBOC) predisposition gene mutations among 882 HBOC high-risk Chinese individuals. | Shao D | Cancer science | 2020 | PMID: 31742824 |
| Germline mutations in Thai patients with nonmucinous epithelial ovarian cancer. | Manchana T | World journal of clinical oncology | 2019 | PMID: 31815095 |
| Spectrum and prevalence of BRCA1/2 germline mutations in Pakistani breast cancer patients: results from a large comprehensive study. | Rashid MU | Hereditary cancer in clinical practice | 2019 | PMID: 31528241 |
| 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 |
| Comprehensive analysis of serum tumor markers and BRCA1/2 germline mutations in Chinese ovarian cancer patients. | Deng H | Molecular genetics & genomic medicine | 2019 | PMID: 30972954 |
| Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China. | Deng M | International journal of cancer | 2019 | PMID: 30720863 |
| 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 |
| 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 mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer. | Li JY | International journal of cancer | 2019 | PMID: 29752822 |
| BRCA germline mutations in an unselected nationwide cohort of Chinese patients with ovarian cancer and healthy controls. | Li A | Gynecologic oncology | 2018 | PMID: 30078507 |
| The germline mutational landscape of BRCA1 and BRCA2 in Brazil. | Palmero EI | Scientific reports | 2018 | PMID: 29907814 |
| Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations. | Singh J | Breast cancer research and treatment | 2018 | PMID: 29470806 |
| 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 |
| Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia. | Wen WX | Journal of medical genetics | 2018 | PMID: 28993434 |
| A multi-gene panel study in hereditary breast and ovarian cancer in Colombia. | Cock-Rada AM | Familial cancer | 2018 | PMID: 28528518 |
| 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 |
| Molecular characterization and clinical interpretation of BRCA1/BRCA2 variants in families from Murcia (south-eastern Spain) with hereditary breast and ovarian cancer: clinical-pathological features in BRCA carriers and non-carriers. | Gabaldó Barrios X | Familial cancer | 2017 | PMID: 28477318 |
| BRCA1 and BRCA2 mutations in ovarian cancer patients from China: ethnic-related mutations in BRCA1 associated with an increased risk of ovarian cancer. | Shi T | International journal of cancer | 2017 | PMID: 28176296 |
| Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women. | Rebbeck TR | Breast cancer research : BCR | 2016 | PMID: 27836010 |
| High prevalence and predominance of BRCA1 germline mutations in Pakistani triple-negative breast cancer patients. | Rashid MU | BMC cancer | 2016 | PMID: 27553291 |
| Mutation detection rates associated with specific selection criteria for BRCA1/2 testing in 1854 high-risk families: A monocentric Italian study. | Azzollini J | European journal of internal medicine | 2016 | PMID: 27062684 |
| Multiple gene sequencing for risk assessment in patients with early-onset or familial breast cancer. | Lin PH | Oncotarget | 2016 | PMID: 26824983 |
| Identification of germline alterations in breast cancer predisposition genes among Malaysian breast cancer patients using panel testing. | Ng PS | Clinical genetics | 2016 | PMID: 26757417 |
| 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 |
| Mutational analysis of BRCA1 and BRCA2 in hereditary breast and ovarian cancer families from Asturias (Northern Spain). | Blay P | BMC cancer | 2013 | PMID: 23683081 |
| Novel and recurrent BRCA1/BRCA2 mutations in early onset and familial breast and ovarian cancer detected in the Program of Genetic Counseling in Cancer of Valencian Community (eastern Spain). Relationship of family phenotypes with mutation prevalence. | de Juan Jiménez I | Familial cancer | 2013 | PMID: 23479189 |
| Screening of 185DelAG, 1014DelGT and 3889DelAG BRCA1 mutations in breast cancer patients from North-East India. | Hansa J | Asian Pacific journal of cancer prevention : APJCP | 2012 | PMID: 23317271 |
| 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 |
| Evaluation of BRCA1 and BRCA2 mutations and risk-prediction models in a typical Asian country (Malaysia) with a relatively low incidence of breast cancer. | Thirthagiri E | Breast cancer research : BCR | 2008 | PMID: 18627636 |
| The spectrum and incidence of BRCA1 pathogenic mutations in Slovak breast/ovarian cancer families. | Konecny M | Neoplasma | 2007 | PMID: 17319787 |
| A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting. | van der Hout AH | Human mutation | 2006 | PMID: 16683254 |
| Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations. | Judkins T | Cancer research | 2005 | PMID: 16267036 |
| Nonsense-mediated mRNA decay: terminating erroneous gene expression. | Baker KE | Current opinion in cell biology | 2004 | PMID: 15145354 |
| Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan. | Liede A | American journal of human genetics | 2002 | PMID: 12181777 |
| De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2 mutation. | Tesoriero A | American journal of human genetics | 1999 | PMID: 10417300 |
| Mutations and polymorphisms in the familial early-onset breast cancer (BRCA1) gene. Breast Cancer Information Core. | Couch FJ | Human mutation | 1996 | PMID: 8807330 |
| Mutation analysis of the BRCA1 gene in ovarian cancers. | Takahashi H | Cancer research | 1995 | PMID: 7606717 |
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Text-mined citations for rs80357579 ...
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Record last updated Nov 10, 2024
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