Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_007294.4(BRCA1):c.556T>G(p.Ser186Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,192 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic 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. S186Y) 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 Uncertain_significance. Variant got 2 ACMG points.
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.901
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:1
Likely benign, no assertion criteria provided
clinical testing
Department of Medical and Surgical Sciences, University of Bologna
Sep 01, 2023
PM2(Supporting)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -
Uncertain significance, criteria provided, single submitter
clinical testing
Counsyl
Dec 29, 2017
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Uncertain significance, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Jul 10, 2023
This missense variant replaces serine with alanine at codon 186 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). Functional studies reported to have examined this variant but the findings were inconclusive (PMID: 25823446, 30219179). This variant has been detected in at least four individuals affected with breast and/or ovarian cancer (PMID: 12845657, 30254663, 35409996; DOI: 10.1515/tjb-2019-0424) and in two individuals affected with colorectal cancer (PMID: 32658311). This variant has been identified in 1/250732 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:2
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Nov 09, 2021
Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of BRCA1-related cancers (de Sanjose 2003, Zuntini 2018, Bahsi 2020); Published functional studies demonstrate reduced ubiquitine ligase activity (Starita 2015); Also known as 675T>G; This variant is associated with the following publications: (PMID: 12845657, 30254663, Bahsi2020[case report], 25823446) -
Uncertain significance, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Dec 05, 2022
The p.S186A variant (also known as c.556T>G), located in coding exon 7 of the BRCA1 gene, results from a T to G substitution at nucleotide position 556. The serine at codon 186 is replaced by alanine, an amino acid with similar properties. This alteration (designated as 675T>G) was detected in an individual who was diagnosed with breast cancer at 28 and whose father was diagnosed with leukemia at 63 (de Sanjosé S, et al. Int. J. Cancer 2003;106(4):588-93). In addition, this alteration was identified in a family who met a regional protocol for BRCA testing (Zuntini R et al. Front Genet, 2018 Sep;9:378). In another study, this alteration was seen in 0/732 breast cancer patients, 2/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Jun 21, 2023
This missense variant replaces serine with alanine at codon 186 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). Functional studies reported to have examined this variant but the findings were inconclusive (PMID: 25823446, 30219179). This variant has been detected in at least four individuals affected with breast and/or ovarian cancer (PMID: 12845657, 30254663, 35409996; DOI: 10.1515/tjb-2019-0424) and in two individuals affected with colorectal cancer (PMID: 32658311). This variant has been identified in 1/250732 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. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Oct 27, 2022
This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 186 of the BRCA1 protein (p.Ser186Ala). This variant is present in population databases (rs397509298, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 12845657). ClinVar contains an entry for this variant (Variation ID: 55633). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Familial cancer of breast Benign:1
Likely benign, criteria provided, single submitter
clinical testing
MGZ Medical Genetics Center
Feb 09, 2024
ACMG codes applied following ENIGMA VCEP rules: BP1_STR, PM2_SUP -
Loss of phosphorylation at S186 (P = 0.0379);Loss of phosphorylation at S186 (P = 0.0379);Loss of phosphorylation at S186 (P = 0.0379);Loss of phosphorylation at S186 (P = 0.0379);.;Loss of phosphorylation at S186 (P = 0.0379);.;.;Loss of phosphorylation at S186 (P = 0.0379);Loss of phosphorylation at S186 (P = 0.0379);.;Loss of phosphorylation at S186 (P = 0.0379);.;