Submissions for variant NM_000059.4(BRCA2):c.6338A>G (p.Asn2113Ser)

gnomAD frequency: 0.00009  dbSNP: rs80358874

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031621	SCV000244466	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 = 0.0000000000117
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080357	SCV000072931	benign	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131603	SCV000186619	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.
GeneDx	RCV000044918	SCV000210628	likely benign	not specified	2017-10-30	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl	RCV000031621	SCV000220794	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-14	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	RCV000131603	SCV000537472	likely benign	Hereditary cancer-predisposing syndrome	2015-04-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034455	SCV000694967	benign	not provided	2017-01-30	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.6338A>G (p.Asn2113Ser) variant involves the alteration of a non-conserved nucleotide, which 3/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 8/119730 (1/14662), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. Multiple publications have cited the variant in affected individuals that have also classified the variant as "benign/neutral." In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. In addition, BRCAshare, a reputable database that incorporates LCA samples indicates the variant co-occurred with another pathogenic BRCA2 variant, c.5576_5579delTTA in 3 individuals, along with an internal LCA sample reports the variant to co-occur with a BRCA1 pathogenic variant, c.68_29delAG. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000034455	SCV000805741	likely benign	not provided	2017-06-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000031621	SCV001139146	likely 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	RCV001798050	SCV002043327	likely benign	Breast and/or ovarian cancer	2021-02-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131603	SCV002536228	likely benign	Hereditary cancer-predisposing syndrome	2021-04-04	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001080357	SCV004014948	likely benign	Hereditary breast ovarian cancer syndrome	2023-03-30	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000044918	SCV004027457	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034455	SCV000043222	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000031621	SCV000054228	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2006-03-08	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031621	SCV000146831	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	RCV001357460	SCV001552939	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asn2113Ser variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs80358874) as "With other allele", ClinVar (classified as benign by Invitae, Ambry Genetics and two other submitters; as likely benign by four submitters; as uncertain significance by three submitters), MutDB, LOVD 3.0 (5x), UMD-LSDB (6x as likely neutral), BIC Database (13x), and in ARUP Laboratories (not pathogenic or of no clinical significance) databases. The variant was not identified in COGR, Cosmic, or the Zhejiang University Database. The variant was identified in control databases in 30 of 271298 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 3 of 6322 chromosomes (freq: 0.0005), Latino in 6 of 33104 chromosomes (freq: 0.0002), European in 5 of 124988 chromosomes (freq: 0.00004), Ashkenazi Jewish in 16 of 9828 chromosomes (freq: 0.002), while the variant was not observed in the African, East Asian, Finnish, or South Asian populations. The p.Asn2113 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) do not predict a difference in splicing. In addition, a systematic genetic assessment and multifactorial probability based model identified the variant has odds in favor of neutrality 1749 and posterior probability of being deleterious 1.17√ó10-11 (Easton 2007, Lindor 2012). 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.