Submissions for variant NM_000059.4(BRCA2):c.7565C>T (p.Ser2522Phe)

gnomAD frequency: 0.00003  dbSNP: rs80358985

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045249	SCV000073262	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000587666	SCV000210429	likely benign	not provided	2019-06-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21120943, 11873550, 19043619, 25782689, 15944772, 19471317, 24504028, 24556621, 29394989, 29884841)
Ambry Genetics	RCV000162600	SCV000213021	likely benign	Hereditary cancer-predisposing syndrome	2020-02-25	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.
Color Diagnostics, LLC DBA Color Health	RCV000162600	SCV000683889	likely benign	Hereditary cancer-predisposing syndrome	2018-06-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587666	SCV000695080	uncertain significance	not provided	2017-07-18	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.7565C>T (p.Ser2522Phe) variant located in the helical domain (Salgado_2005) involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. However, these predictions have yet to be functionally assessed. This variant was found in 1/120720 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). Multiple publications have cited the variant in affected individuals, however, with limited information (ie, lack of co-occurrence and/or cosegregation data). In addition, multiple clinical diagnostic laboratories cite the variant with conflicting classifications "likely benign" or "uncertain significance." Therefore, due to the limited available information, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available (ie, clinical and functional studies).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587666	SCV001133908	uncertain significance	not provided	2023-08-04	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 15944772 (2005), 33471991 (2021)), ovarian cancer (PMID: 24504028 (2014)), and prostate cancer (PMID: 24556621 (2014)). Functional studies indicated that this variant does not disrupt the homology-directed DNA repair function of the BRCA2 protein (PMIDs: 29394989 (2018), 29884841 (2019), 35736817 (2022)). The frequency of this variant in the general population, 0.0000071 (2/282548 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Mendelics	RCV000031686	SCV001139186	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031686	SCV000054293	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-04-27	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031686	SCV000147125	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2013-05-21	no assertion criteria provided	clinical testing
Integrative Tumor Epidemiology Branch, National Institutes of Health	RCV002266908	SCV002549697	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)