Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2BP6_Very_Strong
The NM_007294.4(BRCA1):c.1927A>G(p.Ser643Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S643R) has been classified as Likely 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]
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 -6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 17-43093604-T-C is Benign according to our data. Variant chr17-43093604-T-C is described in ClinVar as Benign. ClinVar VariationId is 54402.Status of the report is reviewed_by_expert_panel, 3 stars.
Breast-ovarian cancer, familial, susceptibility to, 1Uncertain:3Benign:1
Feb 06, 2009
Sharing Clinical Reports Project (SCRP)
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing
- -
Mar 28, 2017
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. -
Jun 18, 2019
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance:Benign
Review Status:reviewed by expert panel
Collection Method:curation
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00055 -
The p.S643G variant (also known as c.1927A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1927. The serine at codon 643 is replaced by glycine, an amino acid with similar properties. In a study of 160 women with a family history of breast and/or ovarian cancer, this variant was reported in one family with a history of breast cancer (Stoppa-Lyonnet D et al. Am. J. Hum. Genet. 1997 May;60:1021-30). This variant has also been reported in a female with breast cancer at age 66, who tested negative for a known familial pathogenic BRCA1 mutation (Dominguez-Valentin M et al. Hered Cancer Clin Pract. 2018 Jan;16:4). This alteration was also classsified as benign in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat. 2019 09;40(9):1557-1578). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Jan 04, 2019
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
not providedUncertain:1
Sep 28, 2015
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant is denoted BRCA1 c.1927A>G at the cDNA level, p.Ser643Gly (S643G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). Using alternate nomenclature, this variant has been previously published as BRCA1 2046A>G, having been observed in a breast cancer family (Stoppa-Lyonnet 1997). BRCA1 Ser643Gly 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 Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ser643Gly occurs at a position where amino acids with properties similar to Serine are tolerated across species and is located in the DNA binding domain (Narod 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Ser643Gly is pathogenic or benign. -
Loss of phosphorylation at S643 (P = 0.0367);Loss of phosphorylation at S643 (P = 0.0367);.;Loss of phosphorylation at S643 (P = 0.0367);.;Loss of phosphorylation at S643 (P = 0.0367);.;