ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9509A>G (p.Asp3170Gly) (rs80359224)

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Total submissions: 13
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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) RCV000114127 SCV000244494 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 = 0.0000264
Ambry Genetics RCV000163018 SCV000213506 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 RCV001573223 SCV000522107 likely benign not provided 2019-02-09 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24323938, 21990134, 17924331, 18951446, 19043619, 18951436, 29394989, 29988080, 29884841)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000440286 SCV000600865 benign not specified 2016-03-04 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000440286 SCV000602759 benign not specified 2016-08-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163018 SCV000689205 likely benign Hereditary cancer-predisposing syndrome 2017-09-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000440286 SCV000695249 likely benign not specified 2019-04-23 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9509A>G (p.Asp3170Gly) results in a non-conservative amino acid change located in the BRCA2, OB3 domain of the encoded protein sequence. Four 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-06 in 251308 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be neutral (Easton 2007 and Lindor 2012). Karchin_2008 classified variant as neutral based on protein likelihood ratio classification. Guidugli_2013 also listed variant as neutral variant. To our knowledge, no occurrence of c.9509A>G in families affected with Hereditary Breast and Ovarian Cancer has been reported. Two publications indicated the functional impact of this variant by HDR assay. One reported this variant effect results in >50%-90% of normal activity and the other one results in >90% of normal activity. Five submitters including and one expert panel have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters including the expert panel have classified the variant as benign (n=3) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign until additional clinical and functional evidence become available.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770737 SCV000902220 likely benign Breast and/or ovarian cancer 2016-12-21 criteria provided, single submitter clinical testing
Invitae RCV001394429 SCV001596113 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-25 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001646954 SCV001852854 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
Breast Cancer Information Core (BIC) (BRCA2) RCV000114127 SCV000147660 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 RCV001354287 SCV001548866 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Asp3170Gly variant was identified in the literature however the frequency of this variant in an affected population was not provided (Easton 2007, Karchin 2008, Guidugli 2018, Lindor 2012). The variant was also identified in dbSNP (ID: rs80359224) as "With other allele", in ClinVar (classified as benign by Ambry Genetics, ENIGMA, Quest Diagnostics, and ARUP Laboratories; as likely benign by Gene Dx, Color; and as uncertain significance by BIC and Integrated Genetics), LOVD 3.0 (7 entries), and UMD-LSDB (2 entries). The variant was identified in control databases in 1 of 246074 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 1 of 111560 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. Several variant model prediction programs conclude that the p.Asp3170Gly variant is not pathogenic (Easton 2007, Karchin 2008, Lindor 2012). A homology-directed DNA repair (HDR) assay in V-C8 cultured cells concluded that this variant was comparable to wild type and was classified as neutral (Guidugli 2018). The Asp3170 residue is not conserved in mammals and four out of five 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 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV001573223 SCV001798761 likely benign not provided no assertion criteria provided clinical testing

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