Submissions for variant NM_000059.4(BRCA2):c.3032C>G (p.Thr1011Arg)

gnomAD frequency: 0.00004  dbSNP: rs80358548

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080499	SCV000072118	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000589304	SCV000210302	uncertain significance	not provided	2023-02-24	criteria provided, single submitter	clinical testing	Published functional studies are inconclusive: spontaneous homologous recombination in human cell line comparable to wildtype, no induction of recombination events in yeast comparable to pathogenic control, impaired binding to APRIN and RAD51 (Balia et al., 2011; Brough et al., 2012; Spugnesi et al., 2013); Observed in individuals with breast and/or ovarian cancer, but also in cancer-free controls (De Sanjose et al., 2003; Balia et al., 2011; Alsop et al., 2012; Gabald Barrios et al., 2017; Terzic et al., 2020; Dorling et al., 2021; Vidra et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3260C>G; This variant is associated with the following publications: (PMID: 23328489, 21671020, 25637381, 12845657, 25948282, 26992456, 24323938, 22293751, 22711857, 28477318, 12442171, 17515904, 12967658, 19747923, 10923033, 29021639, 31422574, 31159747, 32613071, 31131967, 32123317, 33471991, 32377563, 9002670, 22193408, 30630528, 29884841, 35409996)
Ambry Genetics	RCV000164588	SCV000215247	likely benign	Hereditary cancer-predisposing syndrome	2018-07-13	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.
Counsyl	RCV000031396	SCV000488747	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-06-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237440	SCV000694660	uncertain significance	not specified	2024-12-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3032C>G (p.Thr1011Arg) results in a non-conservative amino acid change located in the BRCA2 repeat profile (IPR002093) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250670 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3032C>G has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and related conditions without evidence for causality (e.g. deSanjose_2003, Balia_2011, Alsop_2012, Kluska_2015, Gabaldo_2017, Rosado-jimenez_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Functional studies show inconsistent results, Balia_2011 showed homologous recombination in human cells comparable to WT, Spugnesi_2013 showed that variant of interest did not induce HR (as pathogenic variant controls) and Brough_2012 showed variant fragment of BRCA2 protein with decreased interaction with both APRIN and RAD51 proteins detected via co-IP assay. ClinVar contains an entry for this variant (Variation ID: 37815). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
GeneKor MSA	RCV000164588	SCV000821932	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164588	SCV000910904	likely benign	Hereditary cancer-predisposing syndrome	2016-04-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589304	SCV001133733	uncertain significance	not provided	2024-08-13	criteria provided, single submitter	clinical testing	The BRCA2 c.3032C>G (p.Thr1011Arg) variant has been reported in the published literature in individuals and/or families affected with breast and/or ovarian cancer (PMID: 12845657 (2003), 22711857 (2012), 25948282 (2015), 28477318 (2017), 29021639 (2017), 32613071 (2020), 35409996 (2022)). In a large scale breast cancer association study, the variant was reported in individuals affected with breast cancer as well as reportedly healthy individuals (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/BRCA2). Experimental evidence regarding the effect of this variant on homologous recombination and DNA repair is conflicting (PMID: 21671020 (2011), 23328489 (2013)). In addition, this variant was observed to impair binding to APRIN and RAD51 proteins, which requires further study (PMID: 22293751 (2012)). The frequency of this variant in the general population, 0.00014 (5/34502 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	RCV000031396	SCV001139054	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589304	SCV001148978	uncertain significance	not provided	2016-08-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031396	SCV001428695	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-02-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164588	SCV002533755	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-10	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164588	SCV003850327	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).
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV001080499	SCV005373749	likely benign	Hereditary breast ovarian cancer syndrome	2024-09-09	criteria provided, single submitter	curation	According to the ClinGen ENIGMA BRCA2 v1.1.0 criteria we chose these criteria: PP4 (supporting pathogenic): Combined LR Score: 2.609, BP1 (strong benign): outside functional domain, SpliceAI 0.0 , BS1 (supporting benign): Filter allele frequency (FAF) > 0.002%
Sharing Clinical Reports Project (SCRP)	RCV000031396	SCV000054001	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031396	SCV000146158	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148418	SCV000190117	likely benign	Breast neoplasm	2014-06-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004532437	SCV004728060	likely benign	BRCA2-related disorder	2020-07-07	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).