ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.2416G>C (p.Asp806His) (rs56404215)

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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) RCV000113037 SCV000244430 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 = 0.00008
Invitae RCV001083828 SCV000071999 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-02 criteria provided, single submitter clinical testing
GeneDx RCV000589683 SCV000210577 likely benign not provided 2020-12-17 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 27633797, 24323938, 15001988, 27616075, 17924331, 21990134)
Ambry Genetics RCV000163001 SCV000213489 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.
Counsyl RCV000113037 SCV000220561 likely benign Breast-ovarian cancer, familial 2 2014-07-30 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000043986 SCV000600511 likely benign not specified 2016-08-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000043986 SCV000694606 benign not specified 2019-12-10 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2416G>C (p.Asp806His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 247692 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2416G>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence for causality (e.g. Easton_2007, DeLeener_2008, Mattocks_2010, Kraus_2016, Davis_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported [BRCA1 c.5080G>T, p.Glu1694X (UMD); BRCA1 c.2457_2457delC, p.Ser819=fs (BIC); BRCA2 c.517-2A>G (internal sample)] providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other ClinVar submitters have cited the variant as benign/likely benign, including one expert panel classifed this variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589683 SCV000887774 likely benign not provided 2020-05-08 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769687 SCV000901100 likely benign Breast and/or ovarian cancer 2017-04-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163001 SCV000910796 benign Hereditary cancer-predisposing syndrome 2017-02-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000113037 SCV001273112 uncertain significance Breast-ovarian cancer, familial 2 2017-05-23 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.
Illumina Clinical Services Laboratory,Illumina RCV001115158 SCV001273113 uncertain significance Fanconi anemia, complementation group D1 2017-04-28 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 RCV001642701 SCV001854720 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
Breast Cancer Information Core (BIC) (BRCA2) RCV000113037 SCV000146039 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000113037 SCV000297511 benign Breast-ovarian cancer, familial 2 2011-11-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000043986 SCV000587632 benign not specified 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357888 SCV001553483 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Asp806His variant was identified as benign in in silico prediction models (posterior probability and likelihood ratio model) that integrate multiple forms of genetic evidence (Lindor 2012, Easton 2007 ). The variant was also identified in dbSNP (ID: rs56404215) “With other allele”, ClinVar (benign, reviewed by an expert panel (2015); submitters: benign by ENIGMA, Ambry Genetics and SCRP; LIKELY BENIGN BY Quest Diagnostics Nichols Institute San Juan Capistrano, Invitae, GeneDx, Counsyl; and uncertain significance by BIC), Clinvitae (4x), Genesight-COGR (by 3 clinical labs), LOVD 3.0 (1x), UMD-LSDB (4x as 2-likely neutral , co-occurring with pathogenic BRCA1 variant c.5080G>T/p.Glu1649X), BIC Database (7x, clinical importance unknown, classification pending) and not in Cosmic, MutDB, ARUP Laboratories, and Zhejiang Colon Cancer Database. The variant was identified in control databases in 7 of 274058 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 23966 chromosomes (freq: 0.00004), European Non-Finnish in 6 of 125572 chromosomes (freq: 0.00005), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Asp806 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of His to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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 likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000589683 SCV001740202 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000043986 SCV001905732 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000043986 SCV001957986 benign not specified no assertion criteria provided clinical testing

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