Submissions for variant NM_000059.3(BRCA2):c.6821G>T (p.Gly2274Val) (rs55712212)

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045064	SCV000073077	benign	Hereditary breast and ovarian cancer syndrome	2019-12-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000074551	SCV000108636	likely benign	not specified	2017-10-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000131679	SCV000186715	benign	Hereditary cancer-predisposing syndrome	2014-12-16	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	RCV000077387	SCV000221133	likely benign	Breast-ovarian cancer, familial 2	2015-02-12	criteria provided, single submitter	literature only
PreventionGenetics,PreventionGenetics	RCV000074551	SCV000301768	likely benign	not specified		criteria provided, single submitter	clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C.	RCV000131679	SCV000679722	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000131679	SCV000683816	benign	Hereditary cancer-predisposing syndrome	2015-04-07	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000077387	SCV001268134	likely benign	Breast-ovarian cancer, familial 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Clinical Services Laboratory,Illumina	RCV001110669	SCV001268135	uncertain significance	Fanconi anemia, complementation group D1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV001200387	SCV001371332	likely benign	not provided	2020-05-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001285486	SCV001471921	likely benign	none provided	2020-06-23	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077387	SCV000109184	benign	Breast-ovarian cancer, familial 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077387	SCV000146944	uncertain significance	Breast-ovarian cancer, familial 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Medical Genetics, University Hospital of North Norway	RCV000077387	SCV000301451	likely benign	Breast-ovarian cancer, familial 2	2016-05-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001270288	SCV000592077	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Gly2274Val variant was identified in 8 of 7752 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer and was present in 1 of 2986 control chromosomes (frequency: 0.0003) from healthy individuals (Wagner 1999, Chenevix-Trench 2006, Borg 2010, Morgan 2010, Tamboom 2010, Capanu 2011, Jarhelle 2016, Konecny 2011). The variant was identified in dbSNP (rs55712212) as 'Auwith other allele'Au, ClinVar (classified as likely benign by GeneDx, Counsyl, PreventionGenetics and 4 other submitters; as benign by Color, Invitae, Ambry Genetics and SCRP; and as uncertain significance by BIC, Illumina and 2 other submitters ), LOVD 3.0 (observed 25x) and UMD-LSDB (observed 5x). The variant was identified in control databases in 445 of 267,156 chromosomes (2 homozygous) at a frequency of 0.002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Finnish in 331 of 25,104 chromosomes (freq: 0.01), Other in 9 of 6654 chromosomes (freq: 0.001), European in 104 of 117,702 chromosomes (freq: 0.0008), and Latino in 1 of 35,100 chromosomes (freq: 0.00003); it was not observed in the African, Ashkenazi Jewish, East Asian or South Asian populations. In multiple studies using multifactorial probability models, likelihood ratios predicted the variant to be 'Auneutral'Au (Chenevix-Trench 2006, Lindor 2012). The p.Gly2274 residue is not conserved in mammals 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.
True Health Diagnostics	RCV000131679	SCV000787943	likely benign	Hereditary cancer-predisposing syndrome	2017-08-09	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735591	SCV000863729	uncertain significance	Breast and/or ovarian cancer	2014-02-24	no assertion criteria provided	clinical testing