ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1510C>T (p.Arg504Cys) (rs80357445)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047505 SCV000075518 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 504 of the BRCA1 protein (p.Arg504Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs80357445, ExAC 0.01%). This variant has been observed in an individual with ovarian cancer (PMID: 28525389) and breast cancer (PMID: 26219265). However, in the individual with breast cancer, a likely pathogenic allele was also identified in a different gene (BRCA2), which suggests that this c.1510C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 54277). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000129280 SCV000184040 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-06 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000588157 SCV000293215 uncertain significance not provided 2018-01-04 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1510C>T at the cDNA level, p.Arg504Cys (R504C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). Using alternate nomenclature, this variant would be defined as BRCA1 1629C>T. This variant was observed in an individual with breast cancer, who also carried a variant in BRCA2 which the authors classified as unequivocally deleterious (Ronowicz 2015). Additionally, this variant was observed in at least one family who underwent hereditary BRCA1/2 analysis (Apessos 2018). BRCA1 Arg504Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA1 Arg504Cys is located in the NLS1 of the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, Borg 2010, Paul 2014). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Arg504Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000237007 SCV000591340 uncertain significance not specified 2013-06-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000237007 SCV000600254 uncertain significance not specified 2017-05-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000237007 SCV000698870 uncertain significance not specified 2019-08-30 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1510C>T (p.Arg504Cys) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251052 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1510C>T has been reported in the literature in individuals affected with or being tested for Hereditary Breast and Ovarian Cancer (Judkins_2005, Ronowicz_2015, Apessos_2018, Dougherty_2017). Co-occurrence with other pathogenic variant has been reported (BRCA2, p.Asn3124Ile), providing supporting evidence for a benign role (Ronowicz_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color RCV000129280 SCV000912050 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-30 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111635 SCV000144117 uncertain significance Breast-ovarian cancer, familial 1 2001-10-29 no assertion criteria provided clinical testing
Faculty of Pharmacy,Medical University of Gdansk RCV000207331 SCV000262647 uncertain significance Familial cancer of breast 2014-02-01 no assertion criteria provided research

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