Submissions for variant NM_000059.3(BRCA2):c.4578A>G (p.Thr1526=) (rs202022822)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495149	SCV000578012	benign	Breast-ovarian cancer, familial 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0024 (East Asian), derived from ExAC (2014-12-17).
Ambry Genetics	RCV000163588	SCV000214148	likely benign	Hereditary cancer-predisposing syndrome	2014-07-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV001084558	SCV000261061	benign	Hereditary breast and ovarian cancer syndrome	2020-12-06	criteria provided, single submitter	clinical testing
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University	RCV000240740	SCV000265953	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
GeneDx	RCV000588843	SCV000515708	likely benign	not provided	2020-01-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18431501, 18627636, 27257965, 21601571, 19747923, 10323242)
Color Health, Inc	RCV000163588	SCV000683631	likely benign	Hereditary cancer-predisposing syndrome	2016-02-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588843	SCV000694783	likely benign	not provided	2017-01-18	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.4578A>G (p.Thr1526Thr) variant causes a synonymous change involving a non-conserved nucleotide, 2/5 programs in Alamut predict that this variant may generate a novel 3' splicing acceptor site, one program also predicts the wild-type allele of this variant may generate the same 3' splicing acceptor site, suggesting this predicted effect is unlikely associated with the disease. However, these predictions have yet to be confirmed by functional studies. The variant of interest was observed in a large, broad control population, ExAC, with an allele frequency of 19/120502 (1/6369), predominantly in the East Asian cohort, 19/8642 (1/454), which exceeds the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/3333. Therefore, suggesting this is likely a benign polymorphism found primarily in population(s) of East Asian origin. Multiple publications have cited the variant in affected individuals, however, with limited available information (ie, lack of co-occurrence and cosegregation data). Multiple clinical diagnostic laboratories/reputable databases have classified the variant from "uncertain significance" to "likely benign/benign." Therefore, the variant of interest has been classified as "Likely Benign."
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000427408	SCV000591910	benign	not specified		no assertion criteria provided	clinical testing	The p.Thr1526Thr variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located near a splice junction. The variant has been reported in the literature in 3/472 proband chromosomes from individuals with breast cancer; however, no control chromosomes were tested to establish the frequency of the variant in the general population (Lin_2009, Thirthagiri_2008, Toh_2008). Studies examining the crystal structure of the residue as well as functional studies indicate that it lies within a highly conserved region in the BRC domains of BRCA2 that is involved in the interaction with Rad51, and that it participates in hydrogen bond stabilization of the hairpin complex that forms between BRCA2 and Rad51 (Ochiai_2011, Tal_2009). This variant was previously identified by our lab in two individuals, one individual with a second pathogenic variant, increasing the likelihood this variant is benign. In summary, based on the above information, this variant is classified as benign.