Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_007294.4(BRCA1):c.212G>T(p.Arg71Met) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R71G) 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 18 ACMG points.
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 17 uncertain in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43106457-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 17693.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 17-43106456-C-A is Pathogenic according to our data. Variant chr17-43106456-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43106456-C-A is described in Lovd as [Pathogenic].
Likely pathogenic, criteria provided, single submitter
clinical testing
Ambry Genetics
Jul 15, 2014
The c.212G>T variant (also known as p.R71M), located in coding exon 3 of the BRCA1 gene, results from a G to T substitution at nucleotide position 212. This change occurs in the last base pair of coding exon 3 which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the arginine at codon 71 to methionine, an amino acid with similar properties. <span style="background-color:initial">Two disease-causing mutations, p.R71G and p.R71K, have been described at the same codon <span style="background-color:initial">(Janavièius R. EPMA J. 2010;1(3):397-412;83(4):465-9,Sanz DJ et al. Clin Cancer Res. 2010;16(6):1957-67; Meindl et al. Int J Cancer. 2002;97:472-480)<span style="background-color:initial">.<span style="background-color:initial"> Both the nucleotide and<span style="background-color:initial"> amino acid positions are highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native donor splice site; however, direct evidence is unavailable. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico<span style="background-color:initial"> analyses, respectively. <span style="background-color:initial">Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter
clinical testing
Invitae
Jan 02, 2023
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the c.212G nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 11802209, 21863257, 22505045, 23451180, 29752822). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this variant affects BRCA1 function (PMID: 30209399). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 185705). This variant has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 22984553). This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 71 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 4, which is part of the consensus splice site for this exon. -
not specified Uncertain:1
Uncertain significance, no assertion criteria provided
research
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
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