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
Pathogenic, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Jun 18, 2019
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 -
Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Oct 02, 2015
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not provided Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Oct 29, 2015
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. -
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
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Nov 09, 2019
This sequence change replaces arginine with threonine at codon 1495 of the BRCA1 protein (p.Arg1495Thr). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and threonine. It also falls at the last nucleotide of exon 13 of the BRCA1 coding sequence. For these reasons, this variant has been classified as Pathogenic. Experimental studies evaluating the effect of this sequence change on mRNA splicing have shown that this change results in aberrant splicing, leading to the skipping of exon 13 as well as exons 13-14 (PMID: 24489791, 22505045). In addition, a different variant affecting this nucleotide (c.4484G>T) segregates with disease (PMID: 24607278) and is classified as pathogenic (PMID: 24607278, 10571952, 12915465, 21120943), indicating that this nucleotide is important for normal RNA splicing. This variant has been reported in an individual affected with breast cancer (PMID: 24489791). ClinVar contains an entry for this variant (Variation ID: 245697). This variant is not present in population databases (ExAC no frequency). -