ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8010G>A (p.Ser2670=) (rs146430937)

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Total submissions: 13
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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) RCV000495522 SCV000579152 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 RCV000162665 SCV000213109 likely benign Hereditary cancer-predisposing syndrome 2014-11-04 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 RCV001083953 SCV000253044 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000428428 SCV000512391 benign not specified 2015-05-29 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000428428 SCV000600777 likely benign not specified 2016-12-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162665 SCV000683936 benign Hereditary cancer-predisposing syndrome 2016-03-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586244 SCV000695122 likely benign not provided 2017-05-22 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8010G>A (p.Ser2670Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 11/120304 control chromosomes at a frequency of 0.0000914, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been reported in the literature, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign, with one database citing the variant to co-occur with a pathogenic BRCA1 variant in one individual (BRCA1 c.3228_3229delAG (p.Gly1077AlafsX8)). Taken together, this variant is classified as likely benign.
Counsyl RCV000495522 SCV000785077 uncertain significance Breast-ovarian cancer, familial 2 2017-04-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586244 SCV000889148 likely benign not provided 2016-12-06 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000586244 SCV001148994 likely benign not provided 2019-11-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285373 SCV001471791 likely benign none provided 2020-08-07 criteria provided, single submitter clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735607 SCV000863745 likely benign Breast and/or ovarian cancer 2014-03-06 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000586244 SCV001553667 likely benign not provided no assertion criteria provided clinical testing The BRCA2 p.Ser2670= variant was identified in 2 of 324 proband chromosomes (frequency: 0.006) from individuals or families with breast or ovarian cancer (Muendlein 2015, Zanella 2017). The variant was also identified in dbSNP (ID: rs146430937) as "With other allele”, ClinVar (classified as benign by Invitae, GeneDx and Color; as likely benign by 4 submitters; as uncertain significance by Counsyl), COGR, Cosmic (1x in large intestine tissue), and in UMD-LSDB (12x as neutral), databases. In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (c.3228_3229delAG, p.Gly1077AlafsX8), increasing the likelihood that the p.Ser2670= variant does not have clinical significance. The variant was not identified in BIC Database, ARUP Laboratories, or Zhejiang University databases. The variant was identified in control databases in 16 of 245594 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 14 of 111296 chromosomes (freq: 0.0001), and South Asian in 2 of 30750 chromosomes (freq: 0.00007), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity study shows the variant may disrupt the helical-OB1 interface (Guidugli 2013). The p.Ser2670= 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 addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a 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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