Our verdict is Pathogenic. Variant got 24 ACMG points: 24P and 0B. PS1_Very_StrongPM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):āc.5116G>Cā(p.Gly1706Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1706A) has been classified as Benign.
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 24 ACMG points.
PS1
Transcript NM_007294.4 (BRCA1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 267221
PM1
In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 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 chr17-43063909-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37638.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.891
PP5
Variant 17-43063910-C-G is Pathogenic according to our data. Variant chr17-43063910-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 267219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43063910-C-G is described in Lovd as [Likely_pathogenic].
Likely pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Apr 13, 2021
This missense variant replaces glycine with arginine at codon 1706 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A different missense variant affecting the same codon, c.5117G>A (p.Gly1706Glu), is considered to be disease-causing (ClinVar variation ID 37638), suggesting that glycine at this position is important for protein structure and function. A functional study has shown this variant to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). Functional studies for a different nucleotide variant with the same protein change have shown this variant protein to be defective in transcriptional activation and homology-mediated DNA repair assays (PMID: 30257991, 30458859). This variant has been reported in an individual affected with breast or ovarian cancer (PMID: 25948282) and a different nucleotide variant with the same protein change has been observed in multiple individuals suspected of hereditary breast and ovarian cancer (PMID: 22144684) and who underwent cancer genetic testing (PMID: 28726806). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Jun 23, 2020
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly1706 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15689452, 23867111, 27272900, 15923272, 17308087, 11979449, 17924331). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. This missense change has been reported to affect BRCA1 protein function (PMID: 30209399, 30458859). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 267219). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 1706 of the BRCA1 protein (p.Gly1706Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. -
Breast-ovarian cancer, familial, susceptibility to, 1 Other:1