ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2060A>C (p.Gln687Pro) (rs28897680)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129968 SCV000184792 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA1) RCV000031024 SCV000144283 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Color RCV000129968 SCV000683009 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing
GeneDx RCV000587889 SCV000565959 uncertain significance not provided 2018-08-28 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2060A>C at the cDNA level, p.Gln687Pro (Q687P) at the protein level, and results in the change of a Glutamine to a Proline (CAG>CCG). This variant, also known as BRCA1 2179A>C using alternate nomenclature, has not, to our knowledge, been published in the literature as a germline pathogenic or benign variant; however, it has been reported as a somatic variant in a lung and ovarian tumor (Kan 2010, Ellison 2015). BRCA1 Gln687Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glutamine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Gln687Pro is located in the DNA-binding domain and the RAD50 and STAT1 binding domains (Zhong 1999, Ouchi 2000, Narod 2004). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Gln687Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587889 SCV000698913 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2060A>C (p.Gln687Pro) variant involves the alteration of a non-conserved nucleotide and is not located in some of the known domains in the protein (UniProt, InterPro). However, 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/121354 control chromosomes from ExAC at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). It has been reported in literature in one case with ovarian cancer without strong evidence for or against pathogenicity (Ellison_2015). Majority of submissions (4 out of 5) in ClinVar from clinical diagnostic laboratories/reputable databases consider this variant as uncertain significance. Taken together, this variant is currently classified as Variant of Unknown Significance (VUS).
Invitae RCV000047696 SCV000075709 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-25 criteria provided, single submitter clinical testing This sequence change replaces glutamine with proline at codon 687 of the BRCA1 protein (p.Gln687Pro). The glutamine residue is moderately conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is present in population databases (rs28897680, ExAC 0.001%). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 37443). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Sharing Clinical Reports Project (SCRP) RCV000031024 SCV000053617 likely benign Breast-ovarian cancer, familial 1 2010-03-15 no assertion criteria provided clinical testing

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