Submissions for variant NM_007294.4(BRCA1):c.5522G>A (p.Ser1841Asn)

dbSNP: rs80357368

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236784	SCV000292708	likely pathogenic	not provided	2023-08-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5641G>A; This variant is associated with the following publications: (PMID: 20608970, 17305420, 15235020, 15172985, 16969499, 20378548, 17005433, 10946236, 20516115, 31131967, 25748678, 28781887, 28364669, 30765603, 16786532, 30257991, 25348405, 32377563, 30209399, 32803532, 29884841, 35665744, 35918668, 29752822)
Color Diagnostics, LLC DBA Color Health	RCV000583863	SCV000688640	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-09	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 1841 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant reduces homology-directed DNA repair activity and has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 25748678, 30209399, 30257991). This variant has been reported in two individuals affected with breast or ovarian cancer (PMID: 28364669, 29752822). A multifactorial analysis has reported segregation, co-occurrence, tumor pathology, and family history likelihood ratios for pathogenicity of 14.79, 1.067, 0.089 and 5.97, respectively (PMID: 31131967). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236784	SCV001133640	uncertain significance	not provided	2018-11-09	criteria provided, single submitter	clinical testing
Breast Center, Key Laboratory of Carcinogenesis and Translational Research	RCV001254337	SCV001430322	pathogenic	Hereditary breast ovarian cancer syndrome	2020-05-01	criteria provided, single submitter	clinical testing
Invitae	RCV001254337	SCV001536377	uncertain significance	Hereditary breast ovarian cancer syndrome	2020-10-19	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this variant affects BRCA1 protein function (PMID: 30765603, 28781887, 30209399, 16786532, 20378548, 16969499, 17005433, 25748678, 30257991). This variant has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 28364669, 29752822). ClinVar contains an entry for this variant (Variation ID: 55613). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 1841 of the BRCA1 protein (p.Ser1841Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine.
Ambry Genetics	RCV000583863	SCV002653674	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	The p.S1841N variant (also known as c.5522G>A), located in coding exon 22 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5522. The serine at codon 1841 is replaced by asparagine, an amino acid with highly similar properties. This variant 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). This alteration 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), and was determined to be deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Based on internal structural analysis, p.S1841N is highly disruptive to this region of BRCA1 (Ambry internal data; Gaiser OJ et al. Biochemistry. 2004 Dec;43(51):15983-95). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112694	SCV000145566	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2000-06-12	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112694	SCV001244053	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Center for Precision Medicine, Meizhou People's Hospital	RCV002250546	SCV002520856	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only