Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.850C>T(p.Gln284*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Pathogenic. The variant received 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 17-43094681-G-A is Pathogenic according to our data. Variant chr17-43094681-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 55738.Status of the report is reviewed_by_expert_panel, 3 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.
Molecular Diagnostics Laboratory, Catalan Institute of Oncology
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
PVS1, PM5_PTC_Strong, PM2_Supporting c.850C>T, located in exon 10 (11 according to BIC nomenclature) of the BRCA1 gene, is a nonsense variant expected to result in loss of function by premature protein truncation and nonsense-mediated mRNA decay, p.(Gln284*)(PVS1, PM5_PTC_Strong). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_Supporting). No effect is predicted on splicing by SpliceAI. To our knowledge, no relevant functional studies have been reported for this variant. However, the variant was identified in the following databases: BRCA Exchange (pathogenic: “Variant allele predicted to encode a truncated non-functional protein”), ClinVar (8x pathogenic) and LOVD (7x pathogenic, 1x not provided), as well as in the literature, in several cancer related cohorts. Based on currently available information, c.850C>T is classified as a pathogenic variant according to ClinGen-BRCA1 Guidelines version v1.0.0.
Jan 29, 2025
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The p.Q284* pathogenic mutation (also known as c.850C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 850. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been reported in multiple breast and/or ovarian cancer cohorts (Seymour IJ et al. Breast Cancer Res Treat, 2008 Nov;112:343-9; Wong-Brown MW et al. Breast Cancer Res Treat, 2015 Feb;150:71-80; Shi T et al. Int J Cancer, 2017 05;140:2051-2059; Tedaldi G et al. Oncotarget, 2017 Jul;8:47064-47075; Wen WX et al. J Med Genet, 2018 02;55:97-103; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Palmero EI et al. Sci Rep, 2018 06;8:9188; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Marchetti C et al. Ann Surg Oncol, 2018 Nov;25:3701-3708; Gornjec A et al. BMC Cancer, 2019 Apr;19:296; Concolino P et al. Int J Mol Sci, 2019 Jul;20; Santonocito C et al. Cancers (Basel), 2020 May;12; Quaio CRDC et al. Am J Med Genet C Semin Med Genet, 2020 12;184:955-964). 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.
Hereditary breast ovarian cancer syndromePathogenic:2
Dec 13, 2021
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.850C>T (p.Gln284X) 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 (example: c.928C>T [p.Gln310X], c.1054G>T [p.Glu352X]). The variant allele was found at a frequency of 2.8e-06 in 358032 control chromosomes. c.850C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example: Wong-Brown_2015, Wen_2017, Santonocito_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitter has assessed this variant since 2014, including 1 expert panel and 1 consortium: all submitters have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sep 08, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 55738). This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 28176296, 28993434, 29446198, 30322717, 30702160). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln284*) 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).
not providedPathogenic:1
Apr 19, 2024
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Nonsense 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 969C>T; This variant is associated with the following publications: (PMID: 26187060, 36493725, 28087643, 31336956, 32438681, 28888541, 25682074, 18092194, 25525159, 24578176, 25823446, 30702160, 30322717, 31825140, 29907814, 33258288, 29446198, 28176296, 28993434, 36555431)