ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7559G>A (p.Arg2520Gln) (rs80358982)

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Total submissions: 10
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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 Intact protein function observed in appropriate functional assay(s);Other strong data supporting benign classification
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)
Invitae RCV001080947 SCV000253038 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-01 criteria provided, single submitter clinical testing
Counsyl RCV000082974 SCV000489088 uncertain significance Breast-ovarian cancer, familial 2 2016-08-17 criteria provided, single submitter clinical testing
Color Health, Inc 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 RCV000585960 SCV000695079 likely benign not provided 2016-10-06 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7559G>A (p.Arg2520Gln) variant involves the alteration of a conserved nucleotide and results in a replacement of an Arg with a Gln located in the helical domain of BRCA2. 4/5 in-silico tools predict this variant to be damaging. 5/5 programs in Alamut predict the variant not to affect normal splicing. These splicing predictions have been confirmed by analyzing the RNA from patients carrying this variant (Houdayer_2012). The variant was found in 2/120722 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). UMD reports one patient who carries this variant and BRCA2 c.8485C>T/p.Gln2829X (pathogenic in ClinVar), which suggests the variant to be in the benign spectrum. A functional study showed that the variant increases homology-directed recombination repair (HDR) activity when expressed in BRCA2 deficient cells comparable to wild type (Farrugia_2008) further supporting neutrality. Multiple clinical laboratories/reputable databases provide conflicting classifications, ranging from VUS to benign. Taken all lines of evidence together, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000585960 SCV001470241 uncertain significance not provided 2019-09-13 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000082974 SCV000115048 benign Breast-ovarian cancer, familial 2 2014-02-20 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000082974 SCV000147122 uncertain significance Breast-ovarian cancer, familial 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.

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