Submissions for variant NM_000059.4(BRCA2):c.5768A>C (p.Asp1923Ala)

gnomAD frequency: 0.00088  dbSNP: rs45491005

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031576	SCV001161665	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00310 (African), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195306	SCV000072761	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131532	SCV000186526	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.
GeneDx	RCV001537845	SCV000210371	likely benign	not provided	2021-01-07	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 10800284, 23555315, 21520273, 18284688, 25348012, 25801821, 23704879, 22034289, 20104584)
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031576	SCV000267786	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000195306	SCV000494400	likely benign	Hereditary breast ovarian cancer syndrome	2016-05-16	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.5768A>C (p.Asp1923Ala) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 34/121054 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0032372 (33/10194). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. One co-occurrence with BRCA1 c.2679_2682delGAAA was found in one individual (BRCA Share database). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001537845	SCV000885096	likely benign	not provided	2022-12-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770727	SCV000902207	likely benign	Breast and/or ovarian cancer	2017-08-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131532	SCV000910703	benign	Hereditary cancer-predisposing syndrome	2016-01-07	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000044748	SCV002070376	benign	not specified	2021-03-05	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000195306	SCV002515126	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000131532	SCV002536174	likely benign	Hereditary cancer-predisposing syndrome	2021-02-17	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000195306	SCV004014902	benign	Hereditary breast ovarian cancer syndrome	2023-06-27	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031576	SCV000054182	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2009-02-23	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031576	SCV000146692	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353544	SCV000592000	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asp1923Ala variant was identified in 12 of 5074 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer (Borg 2010, Fackenthal 2012). The variant was also identified in dbSNP (ID: rs45491005) as “With Uncertain significance, other allele”, the ClinVar database (classified as benign by Invitae, Ambry Genetics, SCRP; likely benign by GeneDx, MMGLUM; uncertain significance by BIC), COGR database (classified as uncertain significance by one clinical laboratory), the BIC database (9x with unknown importance) and UMD (29x with a “likely neutral” classification). In UMD the variant was identified with a co-occurring pathogenic BRCA1 (c.2679_2682delGAAA, p.Lys893AsnfsX106) and BRCA2 variants (c.7558C>T, p.Arg2520X), increasing the likelihood that the p.Asp1923Ala variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002), the NHLBI GO Exome Sequencing Project in 13 of 4406 African American alleles, the Exome Aggregation Consortium database (August 8th 2016) and the Genome Aggregation Database (October 3, 2017) in 78 of 276432 chromosomes (freq. 0.0003). The variant was observed in the following populations: in 75 of 24020 African chromosomes (freq. 0.0003), “Other” in 2 of 6450 chromosomes (freq. 0.0003), and Latino in 1 of 34326 chromosomes (freq. 0.00001), but was not seen in Asian, European, or Finnish populations. The p.Asp1923 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. One study predicted the variant to abolish kinase binding; however this was only based on in silico results (Tram 2013). 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001537845	SCV001905786	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001537845	SCV001931090	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001537845	SCV001963913	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001537845	SCV002036173	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541042	SCV004780637	likely benign	BRCA2-related disorder	2019-08-28	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).