ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7985C>A (p.Thr2662Lys) (rs431825362)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129687 SCV000184488 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
Color RCV000129687 SCV000683928 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-04 criteria provided, single submitter clinical testing
Counsyl RCV000082985 SCV000488125 uncertain significance Breast-ovarian cancer, familial 2 2016-02-19 criteria provided, single submitter clinical testing
GeneDx RCV000587063 SCV000329139 uncertain significance not provided 2016-04-15 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7985C>A at the cDNA level, p.Thr2662Lys (T2662K) at the protein level, and results in the change of a Threonine to a Lysine (ACG>AAG). Using alternate nomenclature, this variant would be defined as BRCA2 8213C>A. This variant has been identified in at least one individual with epithelial ovarian cancer and at least one individual with colon cancer with a family history of pancreatic and breast cancer (Alsop 2012, Shirts 2016). Shirts et al (2016) performed RT-PCR on RNA from an affected individual and reported that this variant created an alternate transcript that skipped exon 18. However, this alternate transcript has been seen in controls and therefore, the significance of this finding is unknown (Tesoriero 2005, Walker 2010). BRCA2 Thr2662Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Thr2662Lys occurs at a position that is not conserved and is located in the DNA binding and SHFM1 binding domain (Marston 1999, Yang 2002). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Thr2662Lys is pathogenic or benign. We consider this to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587063 SCV000695114 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7985C>A (p.Thr2662Lys) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing sites. However, ESE finder predicts that this variant may affect multiple ESE binding sites. This prediction was confirmed by RT-PCR in patient's RNA showing skipping of exon 18 (Shirts_2015), which is predicted to lead to a frameshift change. This variant has been reported in one patient with ovarian cancer and one patient with colon cancer, without strong evidence for causality. This variant is absent in 118364 control chromosomes (ExAC). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance except one clinical diagnostic laboratory classified this variant as pathogenic (University of Washington, Shirts_2015). Taken together, this variant is classified as a "Variant of Uncertain Significance - possibly pathogenic, until additional clinical data becomes available.
Invitae RCV000196144 SCV000254217 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 2662 of the BRCA2 protein (p.Thr2662Lys). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with ovarian and colon cancer (PMID: 23633455, 26845104). ClinVar contains an entry for this variant (Variation ID: 96864). 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: "Deleterious"; PolyPhen-2: "Benign"; 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000082985 SCV000296515 uncertain significance Breast-ovarian cancer, familial 2 2016-04-02 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000082985 SCV000115059 uncertain significance Breast-ovarian cancer, familial 2 2011-03-21 no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000210092 SCV000266046 pathogenic Breast-ovarian cancer, familial 1 2015-11-20 criteria provided, single submitter clinical testing This variantis predicted to alter exonic splice enhancers. RT-PCR of RNA showed exon 18 skipping

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