Submissions for variant NM_000059.4(BRCA2):c.4779A>C (p.Glu1593Asp)

gnomAD frequency: 0.00002  dbSNP: rs80358703

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113341	SCV001161663	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 0.00298 (South Asian), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Invitae	RCV001082952	SCV000072504	benign	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129760	SCV000184567	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	RCV000034442	SCV000210609	likely benign	not provided	2020-03-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327, 17503080, 28918466, 28222693, 10923033, 22752604, 22703879, 26469044, 12442273, 27181684, 19656415)
Color Diagnostics, LLC DBA Color Health	RCV000129760	SCV000910667	benign	Hereditary cancer-predisposing syndrome	2016-09-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120321	SCV002066201	likely benign	not specified	2018-07-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129760	SCV002533904	benign	Hereditary cancer-predisposing syndrome	2021-07-01	criteria provided, single submitter	curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034442	SCV003799958	benign	not provided	2022-03-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034442	SCV004010219	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120321	SCV004099929	likely benign	not specified	2023-09-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4779A>C (p.Glu1593Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 250646 control chromosomes, predominantly at a frequency of 0.003 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.66_67delAG, p.Leu22_Glu23LeuValfs), providing supporting evidence for a benign role (BIC database). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as Benign/likely benign (n=8) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004534717	SCV004727639	benign	BRCA2-related disorder	2020-05-21	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).
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034442	SCV000043210	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
ITMI	RCV000120321	SCV000084473	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113341	SCV000146480	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113341	SCV000297529	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2010-09-13	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353910	SCV000591926	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Glu1593Asp variant was identified in 5 of 222 proband chromosomes (frequency: 0.023) from individuals with breast or ovarian cancer and was absent in 88 control chromosomes from these studies (Soumittra 2009, Saxena 2002). The variant was also identified in dbSNP (ID: rs80358703) “With allele of Uncertain significance”, LOVD, and the BIC database (3X with unknown clinical importance). This residue is conserved in mammals but not lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein. 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.
Integrative Tumor Epidemiology Branch, National Institutes of Health	RCV002266911	SCV002549693	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)