Submissions for variant NM_000059.4(BRCA2):c.1644G>A (p.Gln548=)

gnomAD frequency: 0.00007  dbSNP: rs55986646

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112947	SCV000578019	benign	Breast-ovarian cancer, familial, susceptibility to, 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 0.0032 (East Asian), derived from ExAC (2014-12-17).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080641	SCV000071864	benign	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162904	SCV000213391	likely benign	Hereditary cancer-predisposing syndrome	2014-12-10	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	RCV000162904	SCV000683434	benign	Hereditary cancer-predisposing syndrome	2015-11-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501303	SCV000694551	benign	not specified	2019-05-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1644G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00024 in 274202 control chromosomes, predominantly at a frequency of 0.0034 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1644G>A has been reported in the literature in individuals with personal and/or family history of Hereditary Breast and Ovarian Cancer (Hwang_2017, Trujillano_2015, Thirthagiri_2008, Suter_2004). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with a pathogenic variant have been reported (BRCA2 c.1212delT, p.Asn404Lysfs*26; UMD), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000162904	SCV002533247	likely benign	Hereditary cancer-predisposing syndrome	2022-01-14	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000501303	SCV002761144	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000112947	SCV004846942	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-13	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112947	SCV000145904	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2010-09-18	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000112947	SCV000591758	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 p.Gln548Gln variant was identified in the literature in one Chinese family with hereditary breast and ovarian cancer (Thirthagiri 2008); however, control chromosomes from healthy individuals were not evaluated in this study. The variant was also identified in dbSNP (ID: rs rs55986646) “With likely benign allele”, in the 1000 Genomes Project, in 1 of 5000 chromosomes (frequency 0.0002). It was also identified in the Exome Aggregation Consortium (ExAC) database (January 13, 2015) in 28 of 121014 chromosomes (frequency: 0.0002) (or 28 individuals from a population of 8644 East Asian individuals (frequency: 0.003)), and not from European (Non-Finnish)/African/Latino/South Asian/European (Finnish) or other individuals; the Clinvitae database classified the variant as benign/likely benign; ClinVar (4X, classified as a benign by BIC and GeneDX; likely benign by Ambry Genetics), and UMD (2X as a 3-unclassified variant variant, co-occurring with a pathogenic BRCA2 variant (c.1212delT (p.Asn404LysfsX26), increasing the likelihood that the p.Gln548Gln variant does not have clinical significance). The variant was also identified by our laboratory in 3 individuals with breast, and ovarian cancer including one with a co-occurring pathogenic variant (BRCA2 c.246delA), increasing the likelihood the p.Gln548Gln variant does not have clinical significance. The p.Gln548Gln variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. However, four out of five in-silico splicing tools predict abolishment of a 3’ splice site in a region not expected to be involved in splicing, but this information is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratories criteria to be classified as benign.
PreventionGenetics, part of Exact Sciences	RCV004537186	SCV004754462	likely benign	BRCA2-related disorder	2019-07-02	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).