ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4935G>C (p.Arg1645Ser) (rs80357373)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048698 SCV000076711 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 1645 of the BRCA1 protein (p.Arg1645Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (rs80357373, ExAC no frequency). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 16284991, 25136594, 19491284, 24249303, 30287823). ClinVar contains an entry for this variant (Variation ID: 55321). 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 serine amino acid residue is also 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000656790 SCV000210188 uncertain significance not provided 2018-03-06 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4935G>C at the cDNA level, p.Arg1645Ser (R1645S) at the protein level, and results in the change of an Arginine to a Serine (AGG>AGC). This variant, also known as BRCA1 c.5054G>C by alternate nomenclature, has been observed in individuals with breast and/or ovarian cancer (Pal 2005, Haffty 2009, Ruiz 2014, Nakamura 2015). BRCA1 Arg1645Ser was not observed in large population cohorts (Lek 2016). Since Arginine and Serine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Arg1645Ser is located in the BRCT1 domain and a region known to interact with multiple other proteins (Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA1 Arg1645Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000167324 SCV000218174 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-06 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000112427 SCV000489618 uncertain significance Breast-ovarian cancer, familial 1 2016-11-03 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000235133 SCV000591548 uncertain significance not specified 2016-07-21 criteria provided, single submitter clinical testing
Mendelics RCV000048698 SCV000839226 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000167324 SCV000903889 likely benign Hereditary cancer-predisposing syndrome 2016-05-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656790 SCV001133599 uncertain significance not provided 2019-06-05 criteria provided, single submitter clinical testing
Mendelics RCV000112427 SCV001140503 uncertain significance Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112427 SCV000145214 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112427 SCV001243838 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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