Submissions for variant NM_000059.4(BRCA2):c.5070A>C (p.Lys1690Asn)

gnomAD frequency: 0.00023  dbSNP: rs56087561

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113374	SCV000244454	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 = 0.0000000459
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044548	SCV000072561	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000587449	SCV000108618	likely benign	not provided	2020-10-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21952622, 21702907, 11304778, 25948282, 22366370, 28324225, 21990134, 17924331, 17997147, 15172753, 18951446, 24212087, 24323938, 22811390, 12161607, 24489791, 26689913, 19912264, 24504028, 27930734, 18256760, 32444794)
Counsyl	RCV000113374	SCV000154079	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-03-07	criteria provided, single submitter	literature only
Michigan Medical Genetics Laboratories, University of Michigan	RCV000113374	SCV000195987	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162621	SCV000213056	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768596	SCV000219345	likely benign	Breast and/or ovarian cancer	2017-12-20	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000044548	SCV000257611	uncertain significance	Hereditary breast ovarian cancer syndrome	2015-04-17	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000074533	SCV000538493	likely benign	not specified	2023-06-02	criteria provided, single submitter	clinical testing	The p.Lys1690Asn variant in BRCA2 is classified as likely benign because it has been identified in 0.29% (10/3466) of Ashkenazi Jewish chromosomes and 0.031% (21/68012) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1_Supporting
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000074533	SCV000586957	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000074533	SCV000593746	likely benign	not specified	2022-01-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587449	SCV000602858	benign	not provided	2023-03-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162621	SCV000683669	likely benign	Hereditary cancer-predisposing syndrome	2015-04-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587449	SCV000694825	benign	not provided	2016-04-07	criteria provided, single submitter	clinical testing	Variant Summary: The c.5070A>C variant involves a conserved nucleotide in which 4/5 in silico tools predict a damaging outcome, and has a low prevalence in European controls (EVS: 2/8576 chrs and ExAC: 25/72,294 chrs). Though the observed allele frequency in general population is not higher than the maximal expected allele frequency for a BRCA2 pathogenic variant (1/1333) the presence of this variant in controls indicates that this variant might be a rare polymorphism. More importantly, the variant has been reported to co-occur with other deleterious variants in BRCA2 and BRCA1 (4 independent individuals who carry pathogenic variants in each BRCA1 and BRCA2, reported in UMD and BIC), strong evidence that this variantis benign. In addition, it has also been classified as benign by multiple reputable databases and clinical labs, databases and publications (Easton_2007, Lindor_2012 and Whiley_2014). There are no functional studies reported for the variant to date. Multifactorial probability based model also shows the variant to be benign. Taken together, this variant has been classified as Benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000113374	SCV000743303	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000113374	SCV000744461	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-05-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162621	SCV002533922	likely benign	Hereditary cancer-predisposing syndrome	2021-05-07	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000074533	SCV002550341	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504843	SCV002808355	benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2022-03-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587449	SCV002822070	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	BRCA2: BP1
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000162621	SCV004801950	benign	Hereditary cancer-predisposing syndrome	2024-02-02	criteria provided, single submitter	clinical testing	The following ACMG criteria is used: BS1 (FAF > 0.01% in gnomAD), BP1_Strong (SpliceAI: less than or equal to 0.1)
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113374	SCV000146529	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353834	SCV000591937	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	Not expected to have clinical significance. myriad calls a polymorphism (personal communication). 39X in BIC (unknown clinical importance), 12X in UMD and co-occurred with a second pathogenic variant 5X increasing the likelihood the p.Lys1690Asn variant does not have clinical significance. Lindor_2012, Posterior probability of being deleterious = 1.94x10-7 - iarc working group calls class 1 - not pathogenic. Not well conserved in mammals but in-silico software (AlignGVGD, Polyphen-2, SIFT, BLOSUM) do not agree.
Mayo Clinic Laboratories, Mayo Clinic	RCV000587449	SCV000778680	likely benign	not provided	2017-10-16	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000074533	SCV001905875	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000074533	SCV001956538	benign	not specified		no assertion criteria provided	clinical testing
Integrative Tumor Epidemiology Branch, National Institutes of Health	RCV002266907	SCV002549694	uncertain significance	Chordoma	2021-03-22	no assertion criteria provided	research	No impact on ES cell survival or drug sensitivity (no impact on BRCA2 function)
BRCAlab, Lund University	RCV000113374	SCV004243649	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing