Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_007294.4(BRCA1):c.2518A>T(p.Ser840Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. S840G) has been classified as Uncertain significance.
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]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Likely_benign. The variant received -3 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.17092773).
BP6
Variant 17-43093013-T-A is Benign according to our data. Variant chr17-43093013-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 89056.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
Breast-ovarian cancer, familial, susceptibility to, 1Uncertain:2Benign:1
Dec 13, 2023
All of Us Research Program, National Institutes of Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This missense variant replaces serine with cysteine at codon 840 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 been reported in two individuals with personal and/or family history of breast or ovarian cancer (PMID: 21120943, 32438681). This variant has been identified in 3/251094 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. -
Oct 09, 2012
Sharing Clinical Reports Project (SCRP)
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing
- -
Nov 03, 2016
Counsyl
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
The p.S840C variant (also known as c.2518A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 2518. The serine at codon 840 is replaced by cysteine, an amino acid with dissimilar properties. This variant has been observed in breast and/or ovarian cancer cohorts (Caux-Moncoutier V et al. Hum. Mutat., 2011 Mar;32:325-34; Martelotto LG et al. Genome Biol., 2014 Oct;15:484; Santonocito C et al, 2020 May;12). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Mar 23, 2023
University of Washington Department of Laboratory Medicine, University of Washington
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:curation
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
May 26, 2023
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This missense variant replaces serine with cysteine at codon 840 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 been reported in two individuals with personal and/or family history of breast or ovarian cancer (PMID: 21120943, 32438681). This variant has been identified in 3/251094 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 specifiedUncertain:1
May 31, 2017
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant is denoted BRCA1 c.2518A>T at the cDNA level, p.Ser840Cys (S840C) at the protein level, and results in the change of a Serine to a Cysteine (AGT>TGT). Using alternate nomenclature, this variant would be defined as BRCA1 2637A>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ser840Cys 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 Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ser840Cys occurs at a position that is not conserved and is located in the DNA binding domain (Narod 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Ser840Cys is pathogenic or benign. We consider it to be a variant of uncertain significance. -