Submissions for variant NM_000059.4(BRCA2):c.6821G>T (p.Gly2274Val)

gnomAD frequency: 0.00126  dbSNP: rs55712212

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045064	SCV000073077	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001200387	SCV000108636	likely benign	not provided	2020-11-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20104584, 20380699, 9971877, 20127978, 16489001, 21990134, 21203900, 21702907, 27495310, 12601471, 28324225, 27882345, 20167696, 24094589, 25348012, 23555315, 27527004, 26580448, 30611917)
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: 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	RCV000077387	SCV000221133	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-02-12	criteria provided, single submitter	literature only
PreventionGenetics, part of Exact Sciences	RCV004528247	SCV000301768	benign	BRCA2-related disorder	2019-09-04	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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 Diagnostics, LLC DBA Color Health	RCV000131679	SCV000683816	benign	Hereditary cancer-predisposing syndrome	2015-04-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000077387	SCV001268134	likely benign	Breast-ovarian cancer, familial, susceptibility to, 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 Laboratory Services, 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 Center for Human Genetics Tuebingen	RCV001200387	SCV001371332	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	BRCA2: BP1, BP4
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001200387	SCV001471921	benign	not provided	2023-11-17	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735591	SCV002043371	benign	Breast and/or ovarian cancer	2021-03-02	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000074551	SCV002551402	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000077387	SCV002579738	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2021-11-22	criteria provided, single submitter	clinical testing
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV002294006	SCV002587065	uncertain significance	Familial cancer of breast	2022-10-23	criteria provided, single submitter	clinical testing	The BRCA2 c.6821G>T variant was found by WES in heterozygous state in female patient (47 y.o., Caucasian) with bilateral breast cancer. No additional rare candidate variants (Class III-V of pathogenicity) were found. The variant is located in a conserved domain that interacts with HSF2BP (PMID:31242413) and located close to a region that forms lattice contacts [aa 2276–2282](PMID:34373645). The variant is in Genome Aggregation Database (gnomAD) with total MAF 0.001590 (Date of access 17-10-2022) and the frequency is within prevalence of deleterious mutations in BRCA1 and BRCA2 (Mutation Prevalence Tables by Myriad Genetics Laboratories). ClinVar contains entry on this variant (Variation ID: 52199) with multiple submissions evaluating variant as “Likely benign”. Various articles describe variant with conflicting interpretation ranging from “Benign” to “Probably Pathogenic” (PMID: 30611917, 28324225, 27882345, 27527004, 27495310, 26580448, 25348012, 24094589, 23555315, 21702907, 21203900, 20380699, 20167696, 20127978, 20104584, 16489001, 9971877). In silico predictions show “Benign” or “Uncertain” based on calibrated prediction (varsome.com). In accordance with ACMG(2015) criteria this variant is classified as Variant of Uncertain Significance (VUS) with following criteria selected: BP4.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131679	SCV003847479	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Mendelics	RCV000131679	SCV004814102	likely benign	Hereditary cancer-predisposing syndrome	2024-04-08	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077387	SCV000109184	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077387	SCV000146944	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 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
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000074551	SCV001906108	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001200387	SCV001954098	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001200387	SCV001969340	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001200387	SCV002036337	likely benign	not provided		no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000077387	SCV004228433	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS1(Strong)+BP1(Strong)+BP5(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
BRCAlab, Lund University	RCV000077387	SCV004243736	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing