Submissions for variant NM_000059.4(BRCA2):c.8850G>T (p.Lys2950Asn) (rs28897754)

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045642	SCV000073655	benign	Hereditary breast and ovarian cancer syndrome	2020-12-07	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000120366	SCV000202305	likely benign	not specified	2016-03-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000120366	SCV000210674	benign	not specified	2016-09-16	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	RCV000162603	SCV000213027	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	RCV000114008	SCV000220539	benign	Breast-ovarian cancer, familial 2	2014-07-23	criteria provided, single submitter	literature only
Vantari Genetics	RCV000162603	SCV000267026	likely benign	Hereditary cancer-predisposing syndrome	2016-01-06	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories,University of Michigan	RCV000114008	SCV000267822	benign	Breast-ovarian cancer, familial 2	2016-04-21	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000045642	SCV000267849	likely benign	Hereditary breast and ovarian cancer syndrome	2016-04-25	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000114008	SCV000383794	likely benign	Breast-ovarian cancer, familial 2	2018-03-06	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045642	SCV000494346	benign	Hereditary breast and ovarian cancer syndrome	2014-09-26	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000162603	SCV000537411	likely benign	Hereditary cancer-predisposing syndrome	2015-04-07	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency	RCV000120366	SCV000586985	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120366	SCV000593733	likely benign	not specified	2017-03-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001282716	SCV000602821	benign	none provided	2020-07-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000120366	SCV000605776	uncertain significance	not specified	2016-12-21	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Lys2950Asn va riant in BRCA2 has been reported in at least 1 individual with BRCA2-associated cancer (Blay 2013). This variant has also been identified in 0.2% (21/11524) of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs28897754). Computational prediction tools and conservation analysis suggest that the p.Lys2950Asn variant may impact the protein, though t his information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of the p.Lys2950Asn variant is uncertain, its f requency suggests that it is more likely to be benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000114008	SCV000743354	benign	Breast-ovarian cancer, familial 2	2014-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000114008	SCV000744551	benign	Breast-ovarian cancer, familial 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000679194	SCV000805787	likely benign	not provided	2017-03-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000045642	SCV000838886	likely benign	Hereditary breast and ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000114008	SCV001139234	likely benign	Breast-ovarian cancer, familial 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000679194	SCV001148999	likely benign	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001112820	SCV001270519	uncertain significance	Fanconi anemia, complementation group D1	2018-03-06	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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV001170977	SCV001333637	likely benign	Breast and/or ovarian cancer	2018-05-17	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000114008	SCV001368031	likely benign	Breast-ovarian cancer, familial 2	2019-05-09	criteria provided, single submitter	clinical testing	This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: PP3,BP1,BP6.
Research and Development, ARUP Laboratories	RCV001646853	SCV001852816	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
ITMI	RCV000120366	SCV000084518	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114008	SCV000147473	uncertain significance	Breast-ovarian cancer, familial 2	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000114008	SCV000189318	benign	Breast-ovarian cancer, familial 2	2011-02-25	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto	RCV000120366	SCV000587973	benign	not specified	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000120366	SCV000592233	benign	not specified		no assertion criteria provided	clinical testing	The p.Lys2950Asn variant was identified in 17 of 11804 proband chromosomes (frequency: 0.001) from individuals or families with Breast, Ovarian and Prostate Cancers, and was present in 2 of 1166 control chromosomes (frequency: 0.002) from healthy individuals (Diez_2003_12955716, Spurdle_2008_18375895, Akbari_2011_21965345, Beristain_2007_17262179, Borg_2010_20104584, Edwards_2003_12474142, Esteban-Cardenosa_2004_14684619, Gayther_2000_10969800, Miramar_2008_18176857, Romano_2007, Schoumacher_2001_11400546, Soegaard_2008_18559594, Soegaard_2008_18559594, Cavallone_2010_20694749). The variant was also identified in dbSNP (ID: rs28897754) “With Likely benign allele”, with a minor allele frequency of 0.0012(1000 Genomes Project) and with an average heterozygosity score with standard error of 0.002+/-0.035, increasing the likelihood that this is a benign variant. In NHLBI Exome Sequencing Project (Exome Variant Server) the variant was identified in 7 of 8600 European Americans and was not found in African Americans. In Exome Aggregation Consortium (ExAC) database the variant was identified in 21 of 11524 Latino alleles, 54 of 66378 European (Non Finnish) alleles, 5 of 6610 of Europeans (Finnish) alleles, increasing the likelihood this variant is a low frequency benign polymorphism in certain populations of origin. The variant was identified in the ClinVar database with conflicting classifications. It was classified as a benign variant by the Sharing Clinical Reports Project, (derived from Myriad reports), Ambry Genetics, Counsyl and Invitae; as likely benign by Emory Genetics, CHEO and GeneDX; as uncertain significance by BIC. The variant was identified in the BIC database (111X with unknown clinical importance), and in UMD (78X as a neutral variant). In UMD the variant was identified with co-occurring pathogenic BRCA1 and BRCA2 variants (BRCA1:c.1483_1498del (p.Glu495IlefsX3), c.IVS5+2T>C, c.34C>T (p.Gln12X), c.3841C>T (p.Gln1281X), c.70T>C (p.Cys24Arg), c.IVS5+3A>G (c.212+3A>G); BRCA2: c.8904delC (p.Val2969CysfsX7), c.7007G>A (p.Arg2336His)), increasing the likelihood that the p.Lys2950Asn variant does not have clinical significance. The p.Lys2950 residue is conserved across mammals and lower organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the Asn (asparagine) variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000114008	SCV000733326	benign	Breast-ovarian cancer, familial 2		no assertion criteria provided	clinical testing