Submissions for variant NM_000059.4(BRCA2):c.6953G>A (p.Arg2318Gln)

gnomAD frequency: 0.00001  dbSNP: rs80358921

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077390	SCV001161528	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000238
Invitae	RCV001086727	SCV000073109	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131677	SCV000186713	likely benign	Hereditary cancer-predisposing syndrome	2018-06-27	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	RCV000656799	SCV000210409	likely benign	not provided	2019-09-05	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10923033, 21702907, 25452441, 17972171, 25348012, 27153395, 21990134, 16489001, 21990165, 21741379, 22711857, 26941049, 21952622, 25479140, 31131967)
Department of Pathology and Molecular Medicine, Queen's University	RCV000168594	SCV000588112	likely benign	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131677	SCV000903879	likely benign	Hereditary cancer-predisposing syndrome	2016-05-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656799	SCV001133882	likely benign	not provided	2023-04-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000077390	SCV001139164	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735593	SCV002043400	uncertain significance	Breast and/or ovarian cancer	2021-07-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168594	SCV002572212	benign	not specified	2022-08-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6953G>A (p.Arg2318Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250152 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6953G>A has been reported in the literature as a VUS in individuals affected with/undergoing testing for breast and/or ovarian cancer (example, Chenevix-Trench_2018, Hondow_2011, Kote-Jarai_2011, Alsop_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multifactorial probability models have reported a neutral outcome (Lindor_2012). Co-occurrences with other pathogenic variant(s) have been reported in various databases and in the literature (BRCA2 c.2330dup, p.Asp777fs; BRCA1 c.2071delA, p.Arg691fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a predominant consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV004537203	SCV004713909	likely benign	BRCA2-related disorder	2024-02-14	criteria provided, single submitter	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).
Sharing Clinical Reports Project (SCRP)	RCV000077390	SCV000109187	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-03-29	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077390	SCV000146980	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735593	SCV000863731	uncertain significance	Breast and/or ovarian cancer		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354760	SCV001549452	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Arg2318Gln variant was identified in 5 of 12202 proband chromosomes (frequency: 0.0004) from individuals or families with breast, ovarian, prostate, and pancreatic cancer and was not identified in 360 control chromosomes from healthy individuals (Alsop_2012, Kote-Jarai_2011, Couch_2015, Dos Santos Vidal_2016, Grant_2015, Chenevix-Trench_2006). The variant was also identified in the following databases: dbSNP (ID: rs80358921) as “With other allele”, ClinVar and Clinvitae (6x as likely benign by Ambry Genetics, COGR, Invitae, SCRP and as uncertain significance by GeneDx, BIC), LOVD 3.0 (5x), UMD-LSDB (5 entries as uncertain significance and in one case the p.Arg2318Gln variant has been reported as co-occurring with a pathogenic variant of BRCA2 gene (c.2330dup, p.Asp777GlnfsX11), BIC Database (4x), ARUP Laboratories (1x as “class 2-likely not pathogenic or of little clinical significance”). The variant was not identified in Cosmic, MutDB and Zhejiang Colon Cancer Database. The variant was identified in control databases in 2 of 244730 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Latino in 1 of 33426 chromosomes (freq: 0.00003), European Non-Finnish in 1 of 111204 chromosomes (freq: 0.000009); but not observed in the African, Other, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. A functional study showed decreased cell survival and a higher rate of apoptosis in response to cisplatin as compared to wild-type (Warren_2011). The p.Arg2318 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.