ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2050C>T (p.Pro684Ser) (rs397508934)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130395 SCV000185254 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768616 SCV000324813 uncertain significance Breast and/or ovarian cancer 2016-09-18 criteria provided, single submitter clinical testing
Color RCV000130395 SCV000688363 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-12 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000485811 SCV000588037 uncertain significance not specified 2017-04-20 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764123 SCV000895096 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; FANCONI ANEMIA, COMPLEMENTATION GROUP S 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000586501 SCV000568423 uncertain significance not provided 2016-10-17 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2050C>T at the cDNA level, p.Pro684Ser (P684S) at the protein level, and results in the change of a Proline to a Serine (CCA>TCA). Using alternate nomenclature, this variant would be defined as BRCA1 2169C>T. This variant was observed in one individual with breast cancer and one individual with a personal and/or family history of breast and/or ovarian cancer (Lee 2003, Schenkel 2016). BRCA1 Pro684Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Pro684Ser occurs at a position that is not conserved and is located in the DNA binding domain and a region known to interact with RAD50 and STAT1 (Zhong 1999, Ouchi 2000, Narod 2004) . In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Pro684Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586501 SCV000698912 uncertain significance not provided 2016-11-14 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2050C>T (p.Pro684Ser) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121464 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant has been reported in affected individuals in the literature, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000047694 SCV000075707 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 684 of the BRCA1 protein (p.Pro684Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported along with 3 other missense variants in an individual affected with breast cancer (PMID: 12872263). It has also been reported in an individual with a personal or family history of breast and/or ovarian cancer (PMID: 27376475). This variant is also known as 2169C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 54447). 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 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.

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