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

dbSNP: rs80357299

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513284	SCV003441864	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-02-05	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 37681). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 30209399). 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000501320	SCV005199693	likely pathogenic	not provided	2023-04-14	criteria provided, single submitter	clinical testing
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