ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9270C>T (p.Phe3090=) (rs587780873)

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Total submissions: 10
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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) RCV000410788 SCV000579141 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;
GeneDx RCV000124014 SCV000167420 benign not specified 2014-03-19 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.
Ambry Genetics RCV000163089 SCV000213592 likely benign Hereditary cancer-predisposing syndrome 2015-04-21 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724624 SCV000228186 uncertain significance not provided 2015-03-03 criteria provided, single submitter clinical testing
Invitae RCV001081920 SCV000283362 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000410788 SCV000489390 likely benign Breast-ovarian cancer, familial 2 2016-09-29 criteria provided, single submitter clinical testing
Baylor Genetics RCV000474408 SCV000541062 benign Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163089 SCV000684045 likely benign Hereditary cancer-predisposing syndrome 2015-08-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000124014 SCV000695229 likely benign not specified 2017-11-06 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.9270C>T (p.Phe3090Phe) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation Taster predicts a damaging outcome for this variant implicating “splice site changes”, however 5/5 splice prediction tools in Alamut predict no significant impact on normal splicing. ESE finder predicts that this variant may affect the binding site of the splicing factor SRp55, however a functional study found that the variant doesn’t affect splicing in lymphocytes (Quiles 2016). This variant was found in 8/276150 control chromosomes at a frequency of 0.000029, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant, to our knowledge, has not been published in the literature as a germline variant in HBOC affected individuals, however the variant has been reported as a somatic mutation in a serous endometrial carcinoma and malignant melanomas (COSMIC). In addition, multiple clinical diagnostic laboratories classified this variant as benign or likely benign. Taken together, this variant is classified as likely benign.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000724624 SCV001550211 likely benign not provided no assertion criteria provided clinical testing The BRCA2 p.Phe3090= variant was not identified in the literature nor was it identified in the following databases: COGR, MutDB, LOVD 3.0, UMD-LSDB, BIC Database, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs587780873) as “With Uncertain significance, other allele”, ClinVar and Clinvitae (classified as benign by GeneDx and Baylor Miraca Genetics, classified as likely benign by Color Genomics, Ambry Genetics, Invitae, Counsyl and ENIGMA, classified as uncertain significance by Laboratory Corporation of America and EGL Genetic Diagnostics), and in the COSMIC database (reported in one case of serous carcinoma of the endometrium and confirmed somatic in 5 cases of malignant melanoma). The variant was identified in control databases in 8 of 276150 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24000 chromosomes (freq: 0.00004), European Non-Finnish in 6 of 126022 chromosomes (freq: 0.00005), East Asian in 1 of 18836 chromosomes (freq: 0.00005), but not in the Other, Latino, Ashkenazi Jewish, European Finnish, and South Asian populations. 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 upstream of the variant; this is not very predictive of pathogenicity. The p.Phe3090= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In summary, based on the above information this variant is classified as likely benign.

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