ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6613G>A (p.Val2205Met) (rs80358889)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166043 SCV000216804 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000077379 SCV000146891 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769700 SCV000901117 uncertain significance Breast and/or ovarian cancer 2017-03-31 criteria provided, single submitter clinical testing
Color RCV000166043 SCV000902984 likely benign Hereditary cancer-predisposing syndrome 2016-05-12 criteria provided, single submitter clinical testing
Counsyl RCV000077379 SCV000488305 uncertain significance Breast-ovarian cancer, familial 2 2016-02-18 criteria provided, single submitter clinical testing
GeneDx RCV000588118 SCV000210396 uncertain significance not provided 2017-11-24 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6613G>A at the cDNA level, p.Val2205Met (V2205M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). Using alternate nomenclature, this variant would be defined as BRCA2 6841G>A. This variant was observed in at least one individual with breast cancer, one individual with ovarian cancer, and in individuals undergoing testing due to familial breast and ovarian cancer (Borg 2010, Cunningham 2014, Ruiz 2014, Minucci 2015, Apessos 2017). BRCA2 Val2205Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Val2205Met is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Val2205Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000166043 SCV000821945 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588118 SCV000694983 uncertain significance not provided 2017-03-03 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.6613G>A (p.Val2205Met) variant causes a missense change involving the alteration of a non-conserved nucleotide, which 4/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 5/120326 (1/24038), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. Multiple publications have cited the variant in affected individuals (BrC, OvC, HBOC), however, with limited information (ie lack of co-occurrence and cosegregation data). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000195375 SCV000073006 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-10 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 2205 of the BRCA2 protein (p.Val2205Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs80358889, ExAC 0.006%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 20104584, 24504028, 25136594, 26306726, 21520273). ClinVar contains an entry for this variant (Variation ID: 52134). 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 methionine 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, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044993 SCV000600713 uncertain significance not specified 2017-01-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588118 SCV000889106 uncertain significance not provided 2017-01-30 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077379 SCV000109176 uncertain significance Breast-ovarian cancer, familial 2 2008-05-15 no assertion criteria provided clinical testing

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