Submissions for variant NM_007294.4(BRCA1):c.5522G>C (p.Ser1841Thr)

dbSNP: rs80357368

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480419	SCV000572675	uncertain significance	not provided	2017-01-06	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.5522G>C at the cDNA level, p.Ser1841Thr (S1841T) at the protein level, and results in the change of a Serine to a Threonine (AGT>ACT). Using alternate nomenclature, this variant would be defined as BRCA1 5641G>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ser1841Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Threonine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Ser1841Thr occurs at a position that is conserved in mammals and is located in the BRCT 2 Domain and a region known to interact with multiple other proteins (Paul 2014, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Ser1841Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000692105	SCV000819913	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-24	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 423044). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). This variant disrupts the p.Ser1841 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20516115, 23522120, 30209399, 32885271). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1841 of the BRCA1 protein (p.Ser1841Thr). This variant is not present in population databases (gnomAD no frequency).
Color Diagnostics, LLC DBA Color Health	RCV000775939	SCV000910437	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-13	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 1841 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). This variant has been reported to cause loss of BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in one individual affected with cancer with a BRCA1 truncation covariant (PMID: 32963034). This variant has not been identified 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.
Ambry Genetics	RCV000775939	SCV001186202	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	The p.S1841T variant (also known as c.5522G>C), located in coding exon 22 of the BRCA1 gene, results from a G to C substitution at nucleotide position 5522. The serine at codon 1841 is replaced by threonine, an amino acid with similar properties. One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Another alteration at the same codon, p.S1841N (c.5522G>A), has been identified in patient cohorts with breast and ovarian cancer (Ryu JM et al. Breast, 2017 Jun;33:109-116; Li JY et al. Int. J. Cancer, 2019 01;144:281-289), and has been shown to have a detrimental effect on protein stability, structure, and binding in functional assays (Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Petitalot A et al. Mol. Cancer Res., 2019 01;17:54-69). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Brotman Baty Institute, University of Washington	RCV001078024	SCV001244054	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro