Submissions for variant NM_000059.4(BRCA2):c.6803G>A (p.Arg2268Lys)

gnomAD frequency: 0.00020  dbSNP: rs80358906

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086840	SCV000073068	benign	Hereditary breast ovarian cancer syndrome	2024-01-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131556	SCV000186558	benign	Hereditary cancer-predisposing syndrome	2016-08-22	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077385	SCV000195999	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000587611	SCV000210636	likely benign	not provided	2021-06-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23292937, 22682623, 22034289, 23555315, 31131967)
Eurofins Ntd Llc (ga)	RCV000587611	SCV000225158	uncertain significance	not provided	2015-03-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587611	SCV000600719	likely benign	not provided	2022-10-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045055	SCV000694997	likely benign	not specified	2024-03-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6803G>A (p.Arg2268Lys) results in a conservative amino acid change located in the outside of any known functional domain or repeat of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 250550 control chromosomes, predominantly at a frequency of 0.00051 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant has also been observed in a database of unaffected cancer-free individuals of African American ancestry at age greater than 70 (FLOSSIES database). c.6803G>A has been reported in the literature in sequencing studies of individuals affected with Breast and/or Ovarian Cancers (e.g. Dutil_2012, Fackenthal_2012, Haiman_2013, Balmaa_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (BRCA1, c.815_824dupAGCCATGTGG, p.Thr276fsX14) (BIC database), including one publication that reported a co-occurrence with an unspecified deleterious mutation (Dutil_2012) providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27621404, 22682623, 22034289, 23555315). ClinVar contains an entry for this variant (Variation ID: 52191) reporting a majority consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000131556	SCV000902982	likely benign	Hereditary cancer-predisposing syndrome	2016-04-28	criteria provided, single submitter	clinical testing
Mendelics	RCV000077385	SCV001139157	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV001086840	SCV002515136	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000131556	SCV002536268	likely benign	Hereditary cancer-predisposing syndrome	2021-06-17	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131556	SCV003847462	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).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492363	SCV004240344	uncertain significance	Breast and/or ovarian cancer	2022-08-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077385	SCV004844315	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-18	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077385	SCV000109182	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2010-12-28	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077385	SCV000146938	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	RCV001353618	SCV000592075	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Arg2268Lys variant has been previously identified in 1 out of 802 proband chromosomes (frequency 0.001) of individuals with unselected breast cancers, but was not studied in control populations (Fackenthal 2012). It is listed in dbSNP database as coming from a "clinical source" (ID#: rs80358906) with an average heterozygosity of 0.002+/-0.028, increasing the likelihood this variant is benign. However, this variant is also listed in the BIC database three times with unknown clinical importance. The p.Ala2268 residue is conserved in mammals, however in silico computational analyses (SIFT and AignGVGD) do not suggest a high likelihood of impact to the protein. In summary, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more benign role for this variant. This variant is classified as a variant of unknown significance.
PreventionGenetics, part of Exact Sciences	RCV004537201	SCV004721429	likely benign	BRCA2-related disorder	2023-11-05	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).