ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3417G>A (p.Lys1139=) (rs145625991)

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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) RCV000495720 SCV000579107 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;
Invitae RCV001083643 SCV000166165 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000123962 SCV000167354 benign not specified 2014-02-07 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.
Ambry Genetics RCV000162706 SCV000213166 likely benign Hereditary cancer-predisposing syndrome 2014-07-14 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000755222 SCV000602810 benign not provided 2018-01-16 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162706 SCV000683554 likely benign Hereditary cancer-predisposing syndrome 2015-10-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000123962 SCV000916995 likely benign not specified 2019-11-27 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353513 SCV000591859 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Lys1139= variant was identified in 1 of 4206 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer (Borg_2010_20104584). The variant was also identified in dbSNP (ID: rs145625991) “With Uncertain significance, other allele”, ClinVar (classified likely benign, reviewed by an expert panel (2017); submitters: benign by ARUP, Invitae, GeneDx, and likely benign by ENIGMA and Ambry Genetics), Clinvitae (4x), LOVD 3.0 (1x), and UMD-LSDB (7x as 3-UV), and was not identified in GeneInsight-COGR, Cosmic, MutDB, BIC Database, ARUP Laboratories, and Zhejiang Colon Cancer Database. The variant was identified in control databases in 36 of 245756 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 1 of 5472 chromosomes (freq: 0.0002) and Ashkenazi Jewish in 35 of 9842 chromosomes (freq: 0.004), while not observed in the African, Latino, European Non-Finnish, East Asian, European Finnish, and South Asian populations. The variant was also identified by our laboratory in 1 individual with breast cancer. The p.Lys1139= 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; 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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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