Submissions for variant NM_007294.4(BRCA1):c.5504G>C (p.Arg1835Pro)

dbSNP: rs273902776

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160013	SCV000210228	uncertain significance	not provided	2014-02-17	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.5504G>C at the cDNA level, p.Arg1835Pro (R1835P) at the protein level, and results in the change of an Arginine to a Proline (CGA>CCA). In vitro structural and functional assays showed no protein folding defect and normal transcriptional activity, but compromised peptide binding activity and specificity indicating uncertain functional significance (Lee 2010). Subsequently, Coquelle et al. (2011) suggested minimal impact on peptide binding based on structure remodeling. BRCA1 Arg1835Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative substitution in which a positive polar amino acid is replaced with a neutral non-polar one, altering a position that is well conserved throughout evolution and is located in the RAD51 binding domain (Roy 2012). Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Arg1835Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000528269	SCV000636051	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1835 of the BRCA1 protein (p.Arg1835Pro). This variant is present in population databases (rs273902776, gnomAD 0.002%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11802209, 32438681). This variant is also known as 5623G>C. ClinVar contains an entry for this variant (Variation ID: 182172). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 20516115, 21473589, 30765603). 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.
Color Diagnostics, LLC DBA Color Health	RCV000776459	SCV000912004	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with proline at codon 1835 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have reported partial impact on phospho-peptide binding assays and intermediate impact on BRCA1 function in a haploid human cell proliferation assay (PMID: 20516115, 21473589, 31131967). This variant has been reported in an individual affected with breast and/or ovarian cancer and a suspected hereditary breast and ovarian cancer family (PMID: 11802209, 32438681), and a multifactorial analysis has reported a segregation likelihood for pathogenicity of 1.5836 (PMID: 31131967). This variant has been identified in 2/251334 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780999	SCV000918744	uncertain significance	not specified	2018-06-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5504G>C (p.Arg1835Pro) 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 allele was found at a frequency of 8.1e-06 in 246514 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.5504G>C, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Meindl_2002). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Coquelle_2011, Lee_2010). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV000776459	SCV001186171	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-05	criteria provided, single submitter	clinical testing	The p.R1835P variant (also known as c.5504G>C), located in coding exon 22 of the BRCA1 gene, results from a G to C substitution at nucleotide position 5504. The arginine at codon 1835 is replaced by proline, an amino acid with dissimilar properties. This alteration has been detected in 1/989 unrelated individuals from a cohort of German breast/ovarian cancer families (Meindl A et al. Int J Cancer. 2002 Feb 1;97(4):472-80) and in 1/2351 Italian breast and/or ovarian cancer patients (Santonocito C et al. Cancers (Basel), 2020 May;12:). Functional assays on peptide binding showed compromised binding activity and specificity from one paper, while another paper showed only a modest reduction in binding (Lee MS et al. Cancer Res. 2010 Jun 15;70(12):4880-90; Coquelle N et al. Biochemistry. 2011 May 31;50(21):4579-89). A functional protease sensitivity assay showed no folding defect and a transcription assay showed normal activity (Lee MS et al. Cancer Res. 2010 Jun 15;70(12):4880-90). Additional functional studies found that this nucleotide substitution had intermediate function in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222) and had intermediate activity in a transcription activation assay (Woods NT et al. NPJ Genom Med, 2016 Mar;1:). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Additional computational methods showed no effect on function based on structural disposition but did show an effect on function based on conservation (Williams RS et al. J Biol Chem. 2003 Dec 26;278(52):53007-16). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV001072248	SCV004215118	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-26	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000780999	SCV004242794	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Brotman Baty Institute, University of Washington	RCV001072248	SCV001237594	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro