ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5937C>G (p.Ser1979Arg) (rs28897737)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587913 SCV000210375 uncertain significance not provided 2018-12-27 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5937C>G at the cDNA level, p.Ser1979Arg (S1979R) at the protein level, and results in the change of a Serine to an Arginine (AGC>AGG). Using alternate nomenclature, this variant would be defined as BRCA2 6165C>G. This variant was observed in at least one individual with a personal and/or family history of breast and/or ovarian cancer (Caux-Moncoutier 2011). BRCA2 Ser1979Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the seventh BRC repeat and the RAD51 binding domain (Cole 2011, Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Ser1979Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000167183 SCV000218019 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000168414 SCV000219108 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 1979 of the BRCA2 protein (p.Ser1979Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine. This variant is present in population databases (rs28897737, ExAC 0.01%). This variant has been reported in individuals affected with breast cancer (PMID: 21120943, Invitae). However, in one of these individuals a pathogenic allele was also identified in BRCA2, which suggests that this c.5937C>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 38009). 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.
Counsyl RCV000031590 SCV000488008 uncertain significance Breast-ovarian cancer, familial 2 2015-12-11 criteria provided, single submitter clinical testing
Color RCV000167183 SCV000683742 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587913 SCV000694920 uncertain significance not provided 2017-08-10 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5937C>G (p.Ser1979Arg) variant occurs at a non-conserved nucleotide and leads to is a missense mutation that is located in the BRC7 repeat of the BRCA2 repeat region. 5/5 in silico tools predict a damaging outcome for this variant. These in silico predictions have not been confirmed with appropriate in vitro/vivo studies. This variant was found in 3/120730 control chromosomes at a frequency of 0.0000248, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant was reported in the literature in one affected individual without strong evidence for causality (no cosegregation or co-occurrence data provided; Caux-Moncoutier_2011). 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)," until additional information is available.
Sharing Clinical Reports Project (SCRP) RCV000031590 SCV000054196 uncertain significance Breast-ovarian cancer, familial 2 2007-02-15 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031590 SCV000146733 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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