Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_001408406.1(BRCA1):c.790+1_790+4delGTTC variant causes a splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,418 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
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 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.052770447 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.3, offset of 1, new splice context is: aggGTatgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43094736-AGAAC-A is Pathogenic according to our data. Variant chr17-43094736-AGAAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 55705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43094736-AGAAC-A is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5
Aug 18, 2017
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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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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Nov 10, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Dec 30, 1999
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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May 24, 2021
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: case-control
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Hereditary breast ovarian cancer syndrome Pathogenic:3
Nov 01, 2021
Genetics Program, Instituto Nacional de Cancer
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research
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Oct 21, 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.Ser264Metfs*33) 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 (rs80357707, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11857748, 12955716, 23683081, 27425403, 27914478, 29907814). This variant is also known as 910delGTTC, 910del4, and 910_913delGTTC. ClinVar contains an entry for this variant (Variation ID: 55705). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Oct 28, 2022
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.791_794delGTTC (p.Ser264MetfsX33) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 249662 control chromosomes. c.791_794delGTTC has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Rebbeck_2018, Maistro_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:2
Nov 09, 2020
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This frameshift variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individuals with breast cancer and ovarian cancer in the published literature (PMID: 29161300 (2017), 27914478 (2016), 23683081 (2013), 12955716 (2003)). Based on the available information, this variant is classified as pathogenic. -
Aug 02, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; 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 910delGTTC; Observed in individuals with a personal or family history including breast and ovarian cancer (Llort et al., 2002; Alemar et al., 2016; Maistro et al., 2016); This variant is associated with the following publications: (PMID: 27425403, 11857748, 27914478, 29907814, 29161300, 30720243, 31447099) -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.791_794delGTTC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 791 to 794, causing a translational frameshift with a predicted alternate stop codon (p.S264Mfs*33). This alteration has been reported in multiple Spanish and Brazilian HBOC families (Llort G et al. Hum. Mutat. 2002 Mar;19(3):307; Díez O et al. Hum. Mutat. 2003 Oct;22:301-12; Blay P et al. BMC Cancer 2013 May;13:243; Alemar B et al. Cancer Genet. 2016 09;209:417-422; Alemar B et al. PLoS ONE 2017 Nov;12:e0187630; Palmero EI et al. Sci. Rep. 2018 Jun;8:9188). 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. -
Feb 26, 2021
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant deletes 4 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. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in four hereditary breast and ovarian cancer families (PMID: 11857748, 12014998, 23683081, 27425403, 27914478) in which this variant was confirmed present in at least one individual affected with early-onset breast cancer and two individuals affected with ovarian cancer (PMID: 12014998, 27914478). This variant has been identified in 2/249662 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. -