Submissions for variant NM_000059.4(BRCA2):c.3073A>G (p.Lys1025Glu)

gnomAD frequency: 0.00006  dbSNP: rs80358550

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083912	SCV000072125	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131460	SCV000186444	likely benign	Hereditary cancer-predisposing syndrome	2018-05-08	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.
GeneDx	RCV000586348	SCV000210586	likely benign	not provided	2019-12-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32123317, 31131967, 30995915, 28726806, 25348012, 26941049, 22476429, 17679929, 24504028, 25111659)
Department of Pathology and Molecular Medicine, Queen's University	RCV000044112	SCV000588088	uncertain significance	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044112	SCV000694664	likely benign	not specified	2023-08-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3073A>G (p.Lys1025Glu) results in a conservative amino acid change located in the BRCA2 repeat (IPR002093) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250060 control chromosomes, predominantly at a frequency of 9.7e-05 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4.8e-05 vs 0.00075), allowing no conclusion about variant significance. Multiple publications (Cunningham_2014, Lu_2012, Maier _2014, dosSantosVidal_2016) have cited c.3073A>G variant in affected individuals. In particular, one study, Yacoub_2007, cites the variant to occur in a man diagnosed with prostate cancer, whose daughter was diagnosed with breast cancer but did not carry the variant of interest, therefore, indicating the variant does not segregate with disease. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.1360_1361del, (p.Glu453_Ser454insTer), providing supporting evidence for a benign role (internal data). The following publications have been ascertained in the context of this evaluation (PMID: 24504028, 22476429, 25111659, 25348012, 17679929, 26941049, 34178674, 32599251). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) or benign/likely benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV000586348	SCV000805684	uncertain significance	not provided	2018-01-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131460	SCV000910901	benign	Hereditary cancer-predisposing syndrome	2016-04-05	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000586348	SCV001716148	uncertain significance	not provided	2019-11-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131460	SCV002533760	likely benign	Hereditary cancer-predisposing syndrome	2022-01-07	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149675	SCV003838821	uncertain significance	Breast and/or ovarian cancer	2021-08-03	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131460	SCV003850361	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586348	SCV004219566	likely benign	not provided	2022-02-11	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV001083912	SCV005374681	likely benign	Hereditary breast ovarian cancer syndrome	2024-07-08	criteria provided, single submitter	curation	According to the ClinGen ENIGMA BRCA2 v1.1.0 criteria we chose these criteria: BP1 (strong benign): missense variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1)., BS1 (supporting benign): (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer)
Sharing Clinical Reports Project (SCRP)	RCV000077290	SCV000109087	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-03-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077290	SCV000146164	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354029	SCV000591847	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Lys1025Glu variant has been reported as a variant of unknown significance in the BIC (x5) and UMD (x2) databases. It has also been reported once in the literaure in a case report of male breast cancer in a patient receiving leuprolide therapy for prostate cancer (Yacoub_2007_17679929). It has not been previously identified by our laboratory. In addition, the variant is listed in the dbSNP database (ID#:rs80358550) as coming from a "clinical source" but no frequency information was provided, and so the prevalence of this variant in the population is not known. This residue is not conserved in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined at this time. This variant is classified as a variant of unknown significance.