ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1460C>A (p.Ala487Glu) (rs56390402)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001082494 SCV000071825 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131573 SCV000186579 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx RCV000679155 SCV000210560 likely benign not provided 2020-07-10 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22476429, 25248401, 20104584, 18559594, 21990134, 21952622, 27208206, 24763404, 20167696)
Counsyl RCV000031322 SCV000220591 likely benign Breast-ovarian cancer, familial 2 2014-08-12 criteria provided, single submitter literature only
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001281850 SCV000602832 likely benign none provided 2019-11-16 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000131573 SCV000679708 likely benign Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679155 SCV000805653 likely benign not provided 2017-08-17 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131573 SCV000910624 benign Hereditary cancer-predisposing syndrome 2015-12-15 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001109419 SCV001266758 uncertain significance Fanconi anemia, complementation group D1 2018-08-30 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 RCV000031322 SCV001273003 uncertain significance Breast-ovarian cancer, familial 2 2018-08-30 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.
Research and Development, ARUP Laboratories RCV001642262 SCV001854678 likely benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031322 SCV000053927 benign Breast-ovarian cancer, familial 2 2011-03-03 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031322 SCV000145875 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000031322 SCV000591745 likely benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The p.Ala487Glu variant was identified in 4 of 5096 proband chromosomes (frequency: 0.001) from individuals with breast or ovarian cancer (Borg 2010, Lindor 2012, Soegaard 2008); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs56390402), the ClinVar database (classified as a benign variant by Ambry Genetics and the Sharing Clinical Reports Project (derived from Myriad reports); classified as likely benign by GeneDx), the BIC database (21X with unknown clinical importance), and UMD (6X as an unclassified variant). In UMD the variant was identified in one sample with a co-occurring pathogenic BRCA2 variant (c.6816_6820delAAGAG (p.Gly2274AlafsX17)), and in another sample with a co-occurring pathogenic BRCA1 variant (c.4327C>T (p.Arg1443X)), increasing the likelihood that the p.Ala487Glu variant does not have clinical significance. The variant was listed in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 6 of 66248 chromosomes (frequency: 0.00009) from a population of European (Non-Finnish) individuals, and was also found in 1 of 8598 European American chromosomes in the Exome Variant Server ESP project. This low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant occurs outside of the splicing consensus sequence and one of five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a difference in splicing, but this information is not very predictive of pathogenicity. The p.Ala487 residue is not conserved in mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.

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