Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3668_3671dupTTCC(p.Cys1225SerfsTer10) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43091859-G-GGGAA is Pathogenic according to our data. Variant chr17-43091859-G-GGGAA is described in ClinVar as [Pathogenic]. Clinvar id is 54960.Status of the report is reviewed_by_expert_panel, 3 stars.
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5
Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Aug 05, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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May 29, 2002
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Jul 09, 2023
All of Us Research Program, National Institutes of Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant inserts 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.3671_3672insTTCC and 3790ins4. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in at least five individuals affected with breast and ovarian cancer (PMID: 15728167, 22711857, 26718727; Color internal data) and in suspected hereditary breast and ovarian cancer families (PMID: 12698193). This variant has not been identified 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. -
Apr 22, 2016
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation
Variant allele predicted to encode a truncated non-functional protein. -
Hereditary breast ovarian cancer syndrome Pathogenic:3
Jan 31, 2014
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research
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Nov 12, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change creates a premature translational stop signal (p.Cys1225Serfs*10) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 12698193, 15728167, 22711857, 26718727). This variant is also known as 3790ins4. ClinVar contains an entry for this variant (Variation ID: 54960). For these reasons, this variant has been classified as Pathogenic. -
Mar 16, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.3668_3671dupTTCC (p.Cys1225SerfsX10) 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 251296 control chromosomes. c.3668_3671dupTTCC has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Alsop_2012, Scottish-NorthernIrishConsortium_2003, Claus_2005, Evans_2022). These data indicate that the variant is likely to be associated with disease. Seven submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:2Uncertain:1
Jan 09, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This frameshift variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. The frequency of this variant in the general population, 0.0000066 (1/152238 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in several individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 12698193 (2003), 15728167 (2005), 22711857 (2012), 26718727 (2016), 33758026 (2022)). Based on the available information, this variant is classified as pathogenic. -
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Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Aug 13, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Observed in individuals with personal or family history consistent with hereditary breast and ovarian cancer (PMID: 15728167, 22711857, 26718727); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3671_3672insTTCC, 3790insTTCC, and 3790ins4; This variant is associated with the following publications: (PMID: 12112659, 12698193, 22711857, 15728167, 26681312, 23242139, 26315209, 21295272, 26718727, 33758026) -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant inserts 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.3671_3672insTTCC and 3790ins4. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in at least five individuals affected with breast and ovarian cancer (PMID: 12698193, 15728167, 22711857, 26718727; Color internal data). This variant has not been identified 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. -
Dec 04, 2024
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.3668_3671dupTTCC (p.C1225Sfs*10) alteration, located in exon 10 (coding exon 9) of the BRCA1 gene, consists of a duplication of TTCC at position 3668, causing a translational frameshift with a predicted alternate stop codon after 10 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation has been reported in multiple individuals with Hereditary Breast and Ovarian Cancer (HBOC) syndrome (Scottish/Northern Irish BRCAI/BRCA2, 2003; Claus, 2005; Alsop, 2012; Bernards, 2016; Susswein, 2016; Arvai, 2019). Of note, this alteration is also designated as 3790ins4 and 3790insTTCC in the published literature. Based on the available evidence, this alteration is classified as pathogenic. -
Breast and/or ovarian cancer Pathogenic:1
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Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research