Submissions for variant NM_000059.4(BRCA2):c.223G>C (p.Ala75Pro)

gnomAD frequency: 0.00032  dbSNP: rs28897701

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077274	SCV000244429	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 = 0.00000000928
Invitae	RCV000043960	SCV000071973	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000513224	SCV000167398	benign	not provided	2018-11-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24055113, 18559594, 25985138, 21952622, 21520273, 21990134, 22505045, 24323938, 12845657, 27616075, 24728327, 21939546, 20104584, 28678401, 17924331, 28680148, 15307796, 25637381, 27741520, 32123317)
CSER _CC_NCGL, University of Washington	RCV000148426	SCV000190125	likely benign	Breast neoplasm	2014-06-01	criteria provided, single submitter	research
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077274	SCV000195946	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162508	SCV000212899	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768584	SCV000219278	likely benign	Breast and/or ovarian cancer	2019-12-27	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120382	SCV000538480	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple publications classify as VUS/notpathogenic; ExAC: 17/66638 European chromosomes
Baylor Genetics	RCV000457418	SCV000541074	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000513224	SCV000602764	likely benign	not provided	2023-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000513224	SCV000608676	benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS1, BS2
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162508	SCV000679706	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162508	SCV000683473	likely benign	Hereditary cancer-predisposing syndrome	2015-02-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000513224	SCV000805670	likely benign	not provided	2018-10-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000043960	SCV000838723	likely benign	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000077274	SCV001138947	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120382	SCV002068944	likely benign	not specified	2020-03-17	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000043960	SCV002515241	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000162508	SCV002533302	likely benign	Hereditary cancer-predisposing syndrome	2021-03-30	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120382	SCV004027393	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
ITMI	RCV000120382	SCV000084534	not provided	not specified	2013-09-19	no assertion provided	reference population
Sharing Clinical Reports Project (SCRP)	RCV000077274	SCV000109071	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077274	SCV000146403	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	RCV000120382	SCV000591664	benign	not specified		no assertion criteria provided	clinical testing	The BRCA2 p.Ala75Pro variant was identified in 6 of 9140 proband chromosomes (frequency: 0.001) from individuals with breast, ovarian, or prostate cancer (Borg 2010, de SanJose 2003, Kote-Jarai 2011, Soegaard 2008); however, control chromosomes were not analyzed from these studies, thus the prevalence of the variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs28897701) “With non-pathogenic allele”, HGMD, UMD (91X as a neutral variant), and the BIC database (51X with unknown clinical importance). The variant was listed in the NHLBI Exome Sequencing Project in 4 of 8600 European American alleles (frequency: 0.0005), increasing the likelihood that it may be a low frequency benign variant in certain populations. This residue is conserved in mammals; however, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. One functional study found no effect of the variant on mRNA transcript levels as compared to wildtype, and two multifactorial based models predict the variant to be non-pathogenic or of no clinical significance (Muller 2011, Capanu 2011, Lindor 2012). In addition, Myriad classifies this variant as a polymorphism (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120382	SCV001905805	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120382	SCV001957972	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000120382	SCV001976157	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000120382	SCV002036586	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077274	SCV004243670	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing