Submissions for variant NM_000059.4(BRCA2):c.3682A>G (p.Asn1228Asp)

gnomAD frequency: 0.00003  dbSNP: rs28897722

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031433	SCV000244440	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-10	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 = 0.00000548
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044242	SCV000072255	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000587829	SCV000210595	likely benign	not provided	2020-06-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18724707, 27153395, 17924331, 24323938, 26010302, 16847550, 16760289, 21990134, 32444794)
Ambry Genetics	RCV000163003	SCV000213491	benign	Hereditary cancer-predisposing syndrome	2014-11-19	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.
Counsyl	RCV000031433	SCV000220848	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-31	criteria provided, single submitter	literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000044242	SCV000296854	uncertain significance	Hereditary breast ovarian cancer syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163003	SCV000683572	likely benign	Hereditary cancer-predisposing syndrome	2015-03-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160221	SCV000694711	benign	not specified	2020-10-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3682A>G (p.Asn1228Asp) results in a conservative amino acid change located in the BRCA2 repeat of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 249496 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4e-05 vs 0.00075), allowing no conclusion about variant significance. c.3682A>G has been reported in the literature in cohorts of individuals with breast cancer (example, Capalbo_2006, DeBrakeleer_2015, Giannini_2006, Romano_2007, Seymour_2008, Maxwell_2016, Ikeda_2016). 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 for this variant (Lindor_2012). At-least two co-occurrences with another pathogenic variant have been reported in the BIC database (BRCA2 c.6468_6469delTC, p.Ser2156_Gln2157SerIlefs), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function by a high throughput functional screen (Ikegami_2020). These results showed no damaging effect of this variant as measured by tolerance to treatment with PARP inhibitors. Eight clinical diagnostic laboratories and one expert panel (ENIGMA, classification as benign) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=3, likely benign, n=4, VUS, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the absence of conclusive evidence supporting an actionable outcome as outlined above and to reflect the majority consensus classification in the field, the variant was classified as benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000031433	SCV000743288	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031433	SCV000744442	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000587829	SCV000805698	likely benign	not provided	2018-01-24	criteria provided, single submitter	clinical testing
Mendelics	RCV000031433	SCV001139069	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163003	SCV002533812	likely benign	Hereditary cancer-predisposing syndrome	2021-03-14	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000587829	SCV002563162	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	BRCA2: BP4
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031433	SCV004016903	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031433	SCV000054038	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031433	SCV000146277	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000031433	SCV001553912	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 p.Asn1228Asp variant was identified in a minimum of 1 of 146 proband chromosomes (frequency: 0.007) from Italian individuals or families with breast/ovarian cancers (Giannini 2006). Computational methods assessing the pathogenicity of unclassified missense variants includes a posterior probability model/likelihood ratio model found the variant not to be deleterious (Lindor 2012, Easton 2007, Rajasekaran 2008). The variant was also identified in dbSBP (ID: rs28897722) “With other allele”, ClinVar (classified as benign, reviewed by an expert panel (last assessed 2015); submitters: benign by ENIGMA, Invitae, Ambry Genetics, SCRP (Sharing Clinical Reports Project, derived from Myriad reports); likely benign by GeneDx, Counsyl; uncertain significance by BIC and Div of Genomic Diagnostics, Children's Hospital of Philadelphia), Clinvitae (4x), LOVD 3.0 (4x), UMD-LSDB (7x with classification 1-Neutral), BIC Database (7x, unknown clinical importance, classification pending), and ARUP Laboratories (classified 1-not pathogenic or of no clinical significance). The variant was not identified in Genesight-COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database. The variant was identified in control databases in 11 of 275416 chromosomes at a frequency of 0.00004 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Asn1228 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information 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 likely benign.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000160221	SCV001905887	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000160221	SCV001951387	benign	not specified		no assertion criteria provided	clinical testing