Submissions for variant NM_000059.3(BRCA2):c.6706G>A (p.Glu2236Lys) (rs41293503)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165940	SCV000216696	uncertain significance	Hereditary cancer-predisposing syndrome	2018-03-06	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083129	SCV000146913	uncertain significance	Breast-ovarian cancer, familial 2	2004-02-20	no assertion criteria provided	clinical testing
Color	RCV000165940	SCV000683802	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000083129	SCV000785196	uncertain significance	Breast-ovarian cancer, familial 2	2017-05-31	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000763895	SCV000894830	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000216299	SCV000278872	uncertain significance	not provided	2018-11-08	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.6706G>A at the cDNA level, p.Glu2236Lys (E2236K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). Using alternate nomenclature, this variant would be defined as BRCA2 6934G>A. This variant has been observed in individuals with personal and/or family histories of breast and/or ovarian cancer and in at least one individual with early-onset prostate cancer (Kote-Jarai 2011, Moghadasi 2013, Cunningham 2014, Kluska 2015, Lincoln 2015). BRCA2 Glu2236Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Glu2236Lys is not located in a known functional domain. In silico analysis, which includes protein predictors?and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Glu2236Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America	RCV000781142	SCV000919005	uncertain significance	not specified	2018-09-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6706G>A (p.Glu2236Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 246152 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6706G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. However, these data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV000045026	SCV000073039	uncertain significance	Hereditary breast and ovarian cancer syndrome	2018-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 2236 of the BRCA2 protein (p.Glu2236Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs41293503, ExAC 0.01%). This variant has been reported in individuals with breast and/or ovarian cancer, and prostate cancer (PMID: 25948282, 21952622, 24504028). ClinVar contains an entry for this variant (Variation ID: 52165). 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: "Probably 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.
Sharing Clinical Reports Project (SCRP)	RCV000083129	SCV000115203	likely benign	Breast-ovarian cancer, familial 2	2012-05-01	no assertion criteria provided	clinical testing