ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5504G>C (p.Arg1835Pro) (rs273902776)

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Total submissions: 4
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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 and ovarian cancer syndrome 2017-10-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 1835 of the BRCA1 protein (p.Arg1835Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (rs273902776, ExAC no frequency). This variant has been reported in the literature in a family with breast and ovarian cancer (PMID: 11802209). This variant is also known as 5623G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 182172). Experimental studies have shown that this variant, located at the C-terminal BRCT domain, affects the structural conformation and peptide binding activity of the BRCA1 protein (PMID: 20516115, 21473589), but has no impact on transcriptional activity and protease sensitivity in vitro (PMID: 20516115). 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 RCV000776459 SCV000912004 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.

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