ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6338A>G (p.Asn2113Ser) (rs80358874)

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Total submissions: 14
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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 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
Invitae RCV001080357 SCV000072931 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 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: 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 2 2014-10-14 criteria provided, single submitter literature only
Color Health, Inc 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,PreventionGenetics RCV000034455 SCV000805741 likely benign not provided 2017-06-27 criteria provided, single submitter clinical testing
Mendelics RCV000031621 SCV001139146 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642415 SCV001854881 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
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 2 2006-03-08 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031621 SCV000146831 uncertain significance Breast-ovarian cancer, familial 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.

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