Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):c.4484G>C(p.Arg1495Thr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1495K) has been classified 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 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43076488-C-T is described in Lovd as [Pathogenic].
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
PP5
Variant 17-43076488-C-G is Pathogenic according to our data. Variant chr17-43076488-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 245697.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43076488-C-G is described in Lovd as [Pathogenic]. Variant chr17-43076488-C-G is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2
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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Jun 18, 2019
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.993039 -
not provided Pathogenic:1
Oct 29, 2015
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is denoted BRCA1 c.4484G>C at the cDNA level, p.Arg1495Thr (R1495T) at the protein level, and results in the change of an Arginine to a Threonine (AGG>ACG). Using alternate nomenclature, this variant would be defined as BRCA1 4603G>C. This variant was observed in an mRNA in-vitro splicing assay to create two aberrant transcripts, both of which lead to deleterious protein function, one skipping exon 14 and the other skipping exons 14-15 (Whiley 2014). BRCA1 Arg1495Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Arg1495Thr occurs at a position that is not conserved and is located within the SCD domain, the DNA binding domain and within a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider BRCA1 Arg1495Thr to be a pathogenic variant. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This missense variant replaces arginine with threonine at codon 1495 of the BRCA1 protein and alters the conserved guanine nucleotide immediately adjacent to the intron 13 splice donor site. RNA study has shown that this variant causes the out-of-frame skipping of exon 13 and some in-frame skipping of exons 13 and 14 and does not produce full-length transcript (PMID: 24489791). This variant has been reported in at least three suspected hereditary breast and ovarian cancer families (PMID: 22762150, 27425403) and to have segregation and tumor pathology likelihood ratios for pathogenicity of 27.7342 and 9.99856, respectively (PMID: 31131967). Two similar variants at this nucleotide position, c.4484G>T and c.4484G>A, have been reported in individuals and families affected with breast and ovarian cancer (PMID: 10571952, 21120943, 24607278, 27741520, 28637432, 29339979) and shown by RNA analysis to cause out-of-frame skipping of exon 13 (PMID: 10571952, 12915465, 21120943, 22505045, 24607278, 31143303). 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Aug 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change affects codon 1495 of the BRCA1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA1 protein. This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast and ovarian cancer (PMID: 27425403, 30322717). ClinVar contains an entry for this variant (Variation ID: 245697). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 22505045, 24489791). This variant disrupts the c.4484G nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 22711857, 22762150, 23633455, 27741520). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -