ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.3581G>A (p.Gly1194Asp) (rs28897721)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077309 SCV000244439 benign Breast-ovarian cancer, familial 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000646
Invitae RCV001084719 SCV000072240 benign Hereditary breast and ovarian cancer syndrome 2020-11-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131681 SCV000186717 likely benign Hereditary cancer-predisposing syndrome 2018-10-26 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Other data supporting benign classification
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735541 SCV000219329 likely benign Breast and/or ovarian cancer 2017-02-07 criteria provided, single submitter clinical testing
Counsyl RCV000077309 SCV000487793 benign Breast-ovarian cancer, familial 2 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000034439 SCV000518131 likely benign not provided 2020-05-27 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25980754, 24323938, 22703879, 21990134, 17924331, 26689913, 17257844, 27150160, 26155992)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000440462 SCV000694707 benign not specified 2020-11-09 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3581G>A (p.Gly1194Asp) results in a non-conservative amino acid change located in the BRCA2 repeat region of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 252186 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (8.7e-05 vs 0.00075), allowing no conclusion about variant significance. c.3581G>A, has been reported in the literature in individuals affected with Breast and Ovarian Cancer (e.g. Alsop 2012, Musolino 2007), without strong evidence for pathogenicity. The variant was predicted to be neutral with a multifactorial probability model, based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious mutations (Easton 2007). In addition, UMD BRCA2 database classified this variant as 'likely neutral'. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been observed (BRCA2 c.5130_5133delTGTA, p.Y1710* at our laboratory; TP53 c.524G>A , p.R175H in a family with Li-Fraunemi syndrome, Zampiga_2016), providing supporting evidence for a benign role. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=3, likely benign, n=5, VUS, n=1). Based on the lack of any actionable evidence supporting a pathogenic outcome as outlined above, the variant was classified as benign.
Color Health, Inc RCV000131681 SCV000902800 likely benign Hereditary cancer-predisposing syndrome 2015-11-08 criteria provided, single submitter clinical testing
Mendelics RCV000077309 SCV001139068 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001111917 SCV001269525 uncertain significance Fanconi anemia, complementation group D1 2019-05-20 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 RCV000077309 SCV001269526 uncertain significance Breast-ovarian cancer, familial 2 2019-05-20 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.
Research and Development, ARUP Laboratories RCV001642541 SCV001854771 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
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034439 SCV000043207 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000077309 SCV000109106 uncertain significance Breast-ovarian cancer, familial 2 2008-05-02 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077309 SCV000146262 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 RCV000077309 SCV000591870 benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The p.Gly1194Asp variant has been identified in 1 out of 132 proband chromosomes (frequency 0.008) in individuals with breast cancer phenotype; however no normal population controls were included in this study (Musolino 2007). It is also listed in dbSNP database presented “with untested allele” (ID#: rs28897721) while no frequency information is provided, therefore representing a rare allele. The variant is also listed in the BIC database 7x as a variant of unknown clinical significance and 4x in the UMD database as a likely neutral variant and was observed once in conjunction with a second "unclassified variant". The p.Gly1194 residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In addition in silico risk assessment analysis of this variant do not suggest clinical significance (Easton 2007, Lindor 2011). Our laboratory has previously identified this variant in one individual who also had a pathogenic variant in BRCA1 increasing the likelihood this variant is benign. In summary, 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 Benign.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735541 SCV000863679 uncertain significance Breast and/or ovarian cancer no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000440462 SCV001741607 benign not specified no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000440462 SCV001905984 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000440462 SCV001957038 benign not specified no assertion criteria provided clinical testing

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