ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5521A>C (p.Ser1841Arg)

dbSNP: rs80357299
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002513284 SCV003441864 likely pathogenic Hereditary breast ovarian cancer syndrome 2023-06-14 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 23522120, 32885271). It has also been observed to segregate with disease in related individuals. 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. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 30209399). 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. ClinVar contains an entry for this variant (Variation ID: 37681). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1841 of the BRCA1 protein (p.Ser1841Arg).
Sharing Clinical Reports Project (SCRP) RCV000031262 SCV000053866 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2010-05-21 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031262 SCV000145564 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2004-11-25 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto RCV000496641 SCV000587519 uncertain significance not specified 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000501320 SCV000591638 likely pathogenic not provided no assertion criteria provided clinical testing The BRCA1 p.Ser1841Arg variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was identified in dbSNP (rs80357299) as “with likely pathogenic allele”, ClinVar (classified as uncertain significance by BIC, SCRP and Women's College Hospital and likely pathogenic by Lady Davis Institute for Medical Research) and LOVD 3.0 (observed 1x). The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In vitro expression of the variant had a demonstrable effect on BRCA1 protein folding, binding and transactivational activity (Lee 2010). Additionally, the variant co-segregated with disease in a family; it was identified in a patient with ovarian cancer, and segregated in 3 family members, including one prostate cancer and two breast cancer cases (Zhang 2013). The p.Ser1841 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735509 SCV000863647 likely pathogenic Breast and/or ovarian cancer no assertion criteria provided clinical testing
Brotman Baty Institute, University of Washington RCV000031262 SCV001243498 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro
BRCAlab, Lund University RCV000031262 SCV004243902 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2024-01-17 no assertion criteria provided clinical testing

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