ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1644G>A (p.Gln548=) (rs55986646)

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Total submissions: 7
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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 2 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; and frequency 0.0032 (East Asian), derived from ExAC (2014-12-17).
Invitae RCV001080641 SCV000071864 benign Hereditary breast and ovarian cancer syndrome 2019-12-31 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000501303 SCV000591758 benign not specified 2015-06-10 criteria provided, single submitter clinical testing
Color RCV000162904 SCV000683434 benign Hereditary cancer-predisposing syndrome 2015-11-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Breast Cancer Information Core (BIC) (BRCA2) RCV000112947 SCV000145904 benign Breast-ovarian cancer, familial 2 2010-09-18 no assertion criteria provided clinical testing

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