Submissions for variant NM_007294.4(BRCA1):c.5096G>C (p.Arg1699Pro)

dbSNP: rs41293459

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001314422	SCV001504956	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-04-27	criteria provided, single submitter	clinical testing	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: 55397). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1699 of the BRCA1 protein (p.Arg1699Pro). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 28781887). 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 disrupts the p.Arg1699 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11157798, 11504767, 12827452, 16683254, 17574969, 20455026, 21324516, 21356067, 21473589, 22843421, 22889855, 24504028, 24728189, 25452441). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
Ambry Genetics	RCV002336191	SCV002641918	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-04	criteria provided, single submitter	clinical testing	The p.R1699P variant (also known as c.5096G>C), located in coding exon 16 of the BRCA1 gene, results from a G to C substitution at nucleotide position 5096. The arginine at codon 1699 is replaced by proline, an amino acid with dissimilar properties. One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Conversely, this variant acted like-wild type in a transcription activation assay (Woods NT et al. NPJ Genom Med, 2016 Mar;1:). Based on internal structural analysis, R1699P disrupts peptide binding interface (Clapperton JA et al. Nat. Struct. Mol. Biol., 2004 Jun;11:512-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc.	RCV000112496	SCV004018693	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-28	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 30209399, 35196514].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001314422	SCV004121903	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5096G>C (p.Arg1699Pro) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251262 control chromosomes (gnomAD). To our knowledge, no occurrence of c.5096G>C in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one functional study reports experimental evidence evaluating an impact on protein function and showed damaging effect of this variant on homology directed repair (HDR) activity (e.g. Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. In addition, other variants (p.Arg1699Trp, p.Arg1699Gln) in this codon have been classified as pathogenic in out lab, supporting this residual is functional and clinical important for BRCA1. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000112496	SCV004215074	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003884343	SCV004698051	likely pathogenic	Familial cancer of breast	2024-12-09	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PM2_SUP,PP3
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112496	SCV000145311	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2010-12-17	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112496	SCV001244080	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro