ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7994A>G (p.Asp2665Gly) (rs28897745)

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Total submissions: 17
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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) RCV000031716 SCV001161618 benign Breast-ovarian cancer, familial 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 = 2.60E-07
Invitae RCV000045378 SCV000073391 benign Hereditary breast and ovarian cancer syndrome 2020-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129068 SCV000183769 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 RCV000590485 SCV000210663 likely benign not provided 2021-02-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17924331, 20104584, 27741520, 28050887, 28758972, 21120943, 18724707, 21952622, 21702907, 21520273, 22505045, 16489001, 19043619, 21990134, 23108138, 20215541, 12474142, 24916970, 28324225, 18559594, 16826315, 20127978, 16758124, 25682074, 24323938, 29394989, 31131967, 32772980, 32438681, 29884841)
Counsyl RCV000031716 SCV000220998 likely benign Breast-ovarian cancer, familial 2 2014-12-30 criteria provided, single submitter literature only
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768637 SCV000324847 likely benign Breast and/or ovarian cancer 2017-04-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000160248 SCV000538503 uncertain significance not specified 2016-10-20 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 7 reports in HGMD, 3 describe as neutral/nonpathogenic; ClinVar: 5 labs report as B/LB
Color Health, Inc RCV000129068 SCV000683933 likely benign Hereditary cancer-predisposing syndrome 2014-11-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590485 SCV000695116 benign not provided 2016-01-29 criteria provided, single submitter clinical testing
Mendelics RCV000045378 SCV000838864 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000031716 SCV001139203 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001112746 SCV001270437 uncertain significance Fanconi anemia, complementation group D1 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV000031716 SCV001270438 likely benign Breast-ovarian cancer, familial 2 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Research and Development, ARUP Laboratories RCV001642469 SCV001854955 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
Sharing Clinical Reports Project (SCRP) RCV000031716 SCV000054323 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031716 SCV000147244 benign Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353857 SCV000592168 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Asp2665Gly variant was identified in the literature in 6 out of 5644 proband chromosomes (frequency 0.001) from individuals with breast, ovarian and prostate cancers, and was identified in 1 out of 360 control chromosomes (frequency 0.003) (Borg 2010, Chenevix-Trench 2006, Edwards 2003, Evans 2008, Peixoto 2006, Soegaard 2008). The variant was also listed in the dbSNP database (ID#: rs28897745) “With Likely benign allele”, with frequencies of 0.0005 in the 1000 Genomes Project and 0.006 in the HAPMAP-TSI cohort; and was also identified in the Exome Variant Server Exome Sequencing Project with a frequency of 0.0007 in European American alleles, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was identified in the HGMD, LOVD, ClinVar, the BIC database (26X with no clinical importance), and UMD (8X as a neutral variant). In the ClinVar database, the variant was classified as benign by the Sharing Clinical Reports Project (derived from Myriad reports) and Ambry Genetics, and as likely benign by Invitae. In UMD the variant was identified with a co-occurring pathogenic BRCA2 variant (c.3847_3848delGT (p.Val1283LysfsX2)), increasing the likelihood that the p.Asp2665Gly variant does not have clinical significance. p.Asp2665 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Asp2665Gly variant may impact the protein. However, this information is not predictive enough to assume 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; however, this is not very predictive of pathogenicity. One functional assay found the variant had similar levels of homology-directed repair to wild-type BRCA2 (Guidugli 2013), and analysis of a tumour showed loss of the variant, suggesting that it is neutral (Chenevix-Trench 2006 16489001). In addition, multifactorial probability-based models classify the variant as likely non-pathogenic or benign (Chenevix-Trench 2006, Guidugli 2013) and one protein likelihood ratio model predicts the variant to be neutral (Karchin 2008 19043619). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

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