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

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045026	SCV000073039	likely benign	Hereditary breast and ovarian cancer syndrome	2019-12-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000165940	SCV000216696	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-12	criteria provided, single submitter	clinical testing	The p.E2236K variant (also known as c.6706G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 6706. The glutamic acid at codon 2236 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in several European cohorts of breast, ovarian and prostate cancer patients (Kote-Jarai Z et al. Br. J. Cancer, 2011 Oct;105:1230-4; Moghadasi S et al. J. Med. Genet., 2013 Feb;50:74-9; Kluska A et al. BMC Med Genomics, 2015 May;8:19; Cunningham JM et al. Sci Rep, 2014 Feb;4:4026). This alteration was detected in trans with a pathogenic BRCA2 mutation in an individual who did not have a personal or family history that is consistent with or suggestive of Fanconi Anemia (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
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.
Color Health, Inc	RCV000165940	SCV000683802	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-27	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
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.
Illumina Clinical Services Laboratory,Illumina	RCV001109885	SCV001267263	uncertain significance	Fanconi anemia, complementation group D1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina	RCV000083129	SCV001267264	uncertain significance	Breast-ovarian cancer, familial 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sharing Clinical Reports Project (SCRP)	RCV000083129	SCV000115203	likely benign	Breast-ovarian cancer, familial 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083129	SCV000146913	uncertain significance	Breast-ovarian cancer, familial 2	2004-02-20	no assertion criteria provided	clinical testing