Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM5BP4_ModerateBP6
The NM_007294.4(BRCA1):āc.2612C>Gā(p.Pro871Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P871L) 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 Likely_benign. Variant got -1 ACMG points.
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43092919-G-AA is described in ClinVar as [Pathogenic]. Clinvar id is 54620.Status of the report is reviewed_by_expert_panel, 3 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.21153569).
BP6
Variant 17-43092919-G-C is Benign according to our data. Variant chr17-43092919-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 91594.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=3}.
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:1
Likely benign, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Jun 02, 2009
- -
Uncertain significance, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Dec 01, 2023
This missense variant replaces proline with arginine at codon 871 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/282358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Aug 18, 2023
In the published literature, this variant has been reported in an individual with breast cancer (PMID: 29963112 (2018)). The frequency of this variant in the general population, 0.00014 (5/35408 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
May 15, 2019
This variant is associated with the following publications: (PMID: 27983536, 25652403, 30541318) -
Likely benign, criteria provided, single submitter
curation
University of Washington Department of Laboratory Medicine, University of Washington
Mar 23, 2023
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Dec 23, 2021
The p.P871R variant (also known as c.2612C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 2612. The proline at codon 871 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species with leucine as the reference amino acid throughout with the exception of only humans having proline as reference amino acid. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Apr 10, 2024
Variant summary: BRCA1 c.2612C>G (p.Pro871Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251034 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2612C>G has been reported in the literature in individuals affected with breast cancer (example: Sirisena_2018, Cecener_2020). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome The following publications have been ascertained in the context of this evaluation (PMID: 31706072, 29963112). ClinVar contains an entry for this variant (Variation ID: 91594). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter