ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9454G>A (p.Glu3152Lys) (rs80359218)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167823 SCV000073835 likely benign not provided 2019-01-15 criteria provided, single submitter clinical testing
GeneDx RCV000045822 SCV000210687 uncertain significance not specified 2017-05-31 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9454G>A at the cDNA level, p.Glu3152Lys (E3152K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). Using alternate nomenclature, this variant would be defined as BRCA2 9682G>A. This variant has not, to our knowledge, been published as being pathogenic or benign. BRCA2 Glu3152Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu3152Lys occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Glu3152Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000165404 SCV000216131 likely benign Hereditary cancer-predisposing syndrome 2017-07-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification
Integrated Genetics/Laboratory Corporation of America RCV000045822 SCV000695240 likely benign not specified 2018-11-13 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9454G>A (p.Glu3152Lys) results in a conservative amino acid change located in the BRCA2, OB3 of 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 6.1e-05 in 246026 control chromosomes, predominantly at a frequency of 0.00045 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (6.1e-05 vs 0.00075), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.9454G>A in individuals affected with Hereditary Breast and Ovarian Cancer has been reported. The variant was reported to have similar HDR activity compared to wild-type in two independent recently published studies, evidence supporting no damaging effect of this variant (Hart_2018, Guidugli_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, 2 classify as likely benign and one as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
Color RCV000165404 SCV000911043 likely benign Hereditary cancer-predisposing syndrome 2017-06-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000167823 SCV001133981 likely benign not provided 2018-11-02 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077471 SCV000109269 likely benign Breast-ovarian cancer, familial 2 2012-07-25 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077471 SCV000147638 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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