ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.627C>A (p.Leu209=) (rs28897704)

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Total submissions: 8
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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) RCV000495412 SCV000579195 likely benign Breast-ovarian cancer, familial 2 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02;
Ambry Genetics RCV000164486 SCV000215134 likely benign Hereditary cancer-predisposing syndrome 2015-10-09 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
Invitae RCV000199527 SCV000252610 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587319 SCV000694954 likely benign not provided 2017-08-21 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.627C>A (p.Leu209Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool (Mutationtaster) predicts a damaging outcome for this variant, while 5/5 splice prediction tools via Alamut predict no significant impact on splice donor and acceptor sites, which was confirmed by an in vitro (minigene) study (Giacomo_2013). The authors noted that the variant was obtained by PCR amplification from patients genomic DNA, however, no clinical information about the patients, or information about co-segregation and co-occurrence was provided, so from this occurrence we can infer no evidence for pathogenicity. ESE finder predicts that this variant may affect multiple ESE sites; however, these predictions have yet to be confirmed by functional studies. This variant was found in 4/121164 control chromosomes, exclusively occurring in the Non-Finnish subcohort of the ExAC project (in 4/66622 control chromosomes) at an allele frequency of 0.006% which does not exceed the maximal expected allele frequency of a disease causing BRCA2 allele (0.075%). Additionally, 2 co-occurrences with possibly pathogenic BRCA2 variants listed in the UMD database (c.9609C>G (p.Tyr3203X) and c.4398_4402delACATT (p.Leu1466PhefsX2)) further support the variant to be benign. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587319 SCV000889095 benign not provided 2017-10-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000164486 SCV000903469 benign Hereditary cancer-predisposing syndrome 2016-02-24 criteria provided, single submitter clinical testing
GeneDx RCV000587319 SCV001939388 benign not provided 2015-09-18 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23983145)
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000199527 SCV000586918 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-04-14 no assertion criteria provided clinical testing

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