ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6935A>T (p.Asp2312Val) (rs80358916)

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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) RCV000113673 SCV001161534 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 = 0.000027
Invitae RCV000045088 SCV000073101 benign Hereditary breast and ovarian cancer syndrome 2020-11-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000163021 SCV000213509 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000045088 SCV000257615 likely benign Hereditary breast and ovarian cancer syndrome 2015-07-10 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000243078 SCV000301769 likely benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000113673 SCV000383752 likely benign Breast-ovarian cancer, familial 2 2017-04-27 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000328837 SCV000383753 likely benign Fanconi anemia, complementation group D1 2017-04-27 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.
Counsyl RCV000113673 SCV000488811 benign Breast-ovarian cancer, familial 2 2016-07-29 criteria provided, single submitter clinical testing
GeneDx RCV000243078 SCV000516689 benign not specified 2017-12-07 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000163021 SCV000679723 likely benign Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163021 SCV000683829 likely benign Hereditary cancer-predisposing syndrome 2016-07-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586654 SCV000695008 likely benign not provided 2016-06-27 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.6935A>T (p.Asp2312Val) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict damaging outcome for this variant. This variant is only three nucleotides away from the nearest exon-intron boundary and is thus predicted to affect normal splicing. 3/5 splice prediction tools predict a significant impact on normal splicing. But in vitro studies show that this variant does not significantly affect normal splicing (Houdayer_2011, Brandao_2011). This variant was found in 32/113924 control chromosomes (including one homozygote), predominantly observed in the South Asian, subpopulation at a frequency of 0.0016915 (27/15962). This frequency is about 2 times higher than the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian. This variant has been reported in several instances in HBOC patients and/or individuals undergoing BRCA1/2 testing including co-occurrence with another deleterious variant (p.Lys1026Ter) in the same gene, strongly supporting for the benign outcome. Multifactorial probability-based models are also consistent with the benign outcome. Multiple clinical labs have classified this variant as benign/likely benign. Taken together, this variant is currently classified as Likely Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586654 SCV000889116 likely benign not provided 2020-01-16 criteria provided, single submitter clinical testing
Mendelics RCV000113673 SCV001139160 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001646596 SCV001854901 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) RCV000113673 SCV000146971 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 RCV000586654 SCV000592083 likely benign not provided no assertion criteria provided clinical testing The BRCA2 p.Asp2312Val variant was identified in 3 of 4718 proband chromosomes (frequency: 0.0006) from Brazilian, German and Other individuals or families at high risk of breast and ovarian cancers, and was present in 1 of 230 control chromosomes (frequency: 0.004) from healthy elderly Croatian women (Fernandes 2016, Trujillano_2015, Brandao 2011). The variant was identified by Brandao (2011) in an individual from a high-risk breast and/or ovarian cancer family and RT-PCR transcript analysis of lymphocytes from this individual showed an increase in exon12 skipping as compared to normal controls; however, the BRCA2 exon 12 deletion isoform is naturally occurring and the c.6935T allele expressed full-length transcript at similar expression levels compared with the wild-type (WT) allele and control alleles suggesting the variant is likely to be neutral. Li (2009) studied a different variant in this region which was also shown to increase exon 12 skipping, and functional results from this study did not detect any difference between this variant and wild type, suggesting that exon 12 is functionally redundant and missense changes in this region are likely to be neutral. In addition, Li (2009) notes that the peptide encoded by exon 12 does not contain any known important functional motifs; however, this region may have a role in processes that were not assessed. An in silico likelihood-ratio study by Easton (2007) suggests that this variant is neutral. In addition, a splice study using 6 in silico models, with predictions compared to transcript analysis showed the variant does not effect change on splicing (Houdayer 2012). The variant was also identified in dbSNP (ID: rs80358916), ClinVar (with conflicting interpretations of pathogenicity; classified as benign by Ambry Genetics, Counsyl, Invitae; likely benign by Prevention Genetics, Div of Genomic Diagnostics - Children's Hospital of Philadelphia, Illumina Clinical Services, GeneDx; and uncertain significance by BIC), Clinvitae (5X), LOVD 3.0 (4x), UMD-LSDB (10X, 1-neutral), and the BIC Database (5x, clinical importance unknown, classification pending). The variant was not identified in the COGR, Cosmic, ARUP Laboratories, and Zhejiang Colon Cancer Databases. The variant was also identified in control databases in 64 (1 homozygous) of 276074 chromosomes at a frequency of 0.0002 in the following populations: other in 1 of 6424 chromosomes (freq. 0.00016), European in 2 of 126058 chromosomes (freq. 0.000016), Ashkenazi Jewish in 1 of 10110 chromosomes (freq. 0.0001), South Asian in 60 of 30712 chromosomes (freq. 0.0002), increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). The variant was also identified by our laboratory in 3 individuals with breast and ovarian cancer. The p.Asp2312 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Asp2312Val variant occurs in the 3rd last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% 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

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