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

gnomAD frequency: 0.00001  dbSNP: rs56404215

Total submissions: 22

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, susceptibility to, 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 ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000589683	SCV000210577	likely benign	not provided	2021-12-22	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: seen in unaffected individuals, 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, susceptibility to, 2	2014-07-30	criteria provided, single submitter	literature only
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	2023-02-04	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	2019-07-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163001	SCV000910796	benign	Hereditary cancer-predisposing syndrome	2017-02-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000113037	SCV001273112	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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 Laboratory Services, 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.
Sema4, Sema4	RCV000163001	SCV002535499	likely benign	Hereditary cancer-predisposing syndrome	2021-06-03	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000043986	SCV002550305	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541232	SCV004766277	likely benign	BRCA2-related disorder	2019-11-26	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113037	SCV000146039	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113037	SCV000297511	benign	Breast-ovarian cancer, familial, susceptibility to, 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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000043986	SCV001957986	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000043986	SCV001975939	benign	not specified		no assertion criteria provided	clinical testing