Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.1860delT(p.His621MetfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. I620I) has been classified as Likely benign. 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 17-43093670-GA-G is Pathogenic according to our data. Variant chr17-43093670-GA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 182105.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.
The c.1860delT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 1860, causing a translational frameshift with a predicted alternate stop codon (p.H621Mfs*5). 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.
Dec 28, 2020
Color Diagnostics, LLC DBA Color Health
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant deletes 1 nucleotide 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 has been reported in individuals affected with triple-negative breast and ovarian cancer (PMID: 25682074, 26681312, 27083178). 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.
May 20, 2025
Molecular Diagnostics Laboratory, Catalan Institute of Oncology
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
PVS1, PM5_PTC_Strong c.1860del, located in exon 10 (11 in BIC nomenclature) of the BRCA1 gene, consists in the delection of 1 nucleotide, causing a translational frameshift with a predicted alternate stop codon, p.(His621Metfs*5).This alteration is expected to result in loss of function by premature protein truncation and nonsense-mediated mRNA decay (PVS1, PM5_PTC_Strong). It is not present in the population database gnomAD v2.1.1, non-cancer exome dataset. The SpliceAI algorithm predicts no significant impact on splicing. This variant has been reported in the ClinVar database (7x Pathogenic), in the LOVD database (3x pathogenic) and classified as a pathogenic variant in BRCA Exchange database (�2016-09-08: Variant allele predicted to encode a truncated non-functional protein�). Based on currently available information, the variant c.1860del is classified as a pathogenic variant according to ClinGen-BRCA1 and BRCA2 Guidelines version 1.0.0.
not providedPathogenic:2
Jul 25, 2019
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 in large population cohorts (Lek et al., 2016); Reported as pathogenic in ClinVar/in a well-curated database but additional evidence is not available; This variant is associated with the following publications: (PMID: 27083178, 26681312, 29446198, 30262796, 30322717)
Dec 31, 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 affected with breast cancer and ovarian cancer in the published literature (PMID: 27083178 (2016), 26681312 (2015), 30322717 (2018)). This variant has not been reported in large, multi-ethnic general populations. Based on the available information, this variant is classified as pathogenic.
Hereditary breast ovarian cancer syndromePathogenic:1
Nov 24, 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.His621Metfs*5) 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/or ovarian cancer (PMID: 26681312, 27083178). ClinVar contains an entry for this variant (Variation ID: 182105). For these reasons, this variant has been classified as Pathogenic.