ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5644T>C (p.Ser1882Pro) (rs730881538)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000257958 SCV000324857 uncertain significance Breast and/or ovarian cancer 2016-01-26 criteria provided, single submitter clinical testing
Color RCV000772756 SCV000906113 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-06 criteria provided, single submitter clinical testing
GeneDx RCV000590236 SCV000210358 uncertain significance not provided 2016-05-11 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5644T>C at the cDNA level, p.Ser1882Pro (S1882P) at the protein level, and results in the change of a Serine to a Proline (TCA>CCA). Using alternate nomenclature, this variant would be defined as BRCA2 5872T>C. This variant has been observed in at least one individual from a hereditary breast and/or ovarian cancer family (van der Hout 2006). BRCA2 Ser1882Pro 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 Serine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser1882Pro occurs at a position that is not conserved and is located in RAD51 binding domain (Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Ser1882Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590236 SCV000694887 uncertain significance not provided 2017-06-08 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5644T>C (p.Ser1882Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution that does not lie within a known functional domain (InterPro). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.0000083 (1/120634 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been identified in at least 1 HBOC family (van der Hout_HM_2006), but without strong evidence for pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as variant of uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000806443 SCV000946444 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 1882 of the BRCA2 protein (p.Ser1882Pro). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and proline. This variant is present in population databases (rs730881538, ExAC 0.002%). This variant has been observed in a family affected with breast and/or ovarian cancer (PMID: 16683254). ClinVar contains an entry for this variant (Variation ID: 182219). 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 proline 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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