Submissions for variant NM_000059.4(BRCA2):c.7559G>A (p.Arg2520Gln)

gnomAD frequency: 0.00002  dbSNP: rs80358982

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130121	SCV000184953	likely benign	Hereditary cancer-predisposing syndrome	2018-04-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000585960	SCV000210656	likely benign	not provided	2019-08-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25447315, 24323938, 19043619, 18451181, 28591715)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080947	SCV000253038	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000082974	SCV000489088	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-08-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130121	SCV000689054	likely benign	Hereditary cancer-predisposing syndrome	2017-10-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469008	SCV000695079	likely benign	not specified	2024-01-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7559G>A (p.Arg2520Gln) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. These splicing predictions have been confirmed by analyzing the RNA from patients carrying this variant (Houdayer_2012). The variant allele was found at a frequency of 3.6e-05 in 251114 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7559G>A has been reported in the literature in individuals affected with breast cancer (example: Pal_2013 and Rodrguez-Balada_ 2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports HDR assay experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Hu_2022). The following publications have been ascertained in the context of this evaluation (PMID: 19043619, 18451181, 22505045, 35736817, 23320992, 31786208). ClinVar contains an entry for this variant (Variation ID: 96853). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000585960	SCV001470241	likely benign	not provided	2023-09-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000082974	SCV004844429	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-30	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000082974	SCV000115048	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-02-20	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000082974	SCV000147122	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	RCV001354035	SCV000592124	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Arg2520Gln variant was identified in dbSNP (ID: rs80358982), LOVD, COSMIC, the ClinVar database (classified as a benign variant by the Sharing Clinical Reports Project, derived from Myriad reports), the BIC database (2X with unknown clinical importance), and UMD (1X as a UV variant).The p.Arg2520 residue is conserved across mammals and lower organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Arg2520 variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. A functional study by Farrugia (2008) suggested that the variant occurs at an evolutionarily conserved residue and classified the variant as a VUS. This variant displayed substantial increases in homology-directed recombination repair (HDR) activity and maintained the background level of centriole and centrosome amplification found in wild-type cells. Another functional study by Karchin (2008) demonstrated protein likelihood ratio of the variant in favor of protein loss of function and suggested uncertain prediction. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.