ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9116C>T (p.Pro3039Leu) (rs80359167)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045720 SCV000073733 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131718 SCV000186757 likely benign Hereditary cancer-predisposing syndrome 2018-10-10 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
GeneDx RCV000254649 SCV000210680 likely benign not specified 2018-02-05 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.
Michigan Medical Genetics Laboratories,University of Michigan RCV000083154 SCV000267827 likely benign Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000254649 SCV000593758 likely benign not specified 2016-04-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000254649 SCV000600843 likely benign not specified 2016-12-19 criteria provided, single submitter clinical testing
Mendelics RCV000045720 SCV000838895 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759684 SCV000889172 likely benign not provided 2019-12-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131718 SCV000910794 benign Hereditary cancer-predisposing syndrome 2016-07-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000254649 SCV000917011 likely benign not specified 2021-01-07 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9116C>T (p.Pro3039Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. Functional studies confirm these predictions indicating this variant has no effect on mRNA splicing (e.g. Caux-Moncoutier_2009, Houdayer_2012, Menendez_2012, Colombo_2013). The variant allele was found at a frequency of 8.9e-05 in 248254 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (8.9e-05 vs 0.00075), allowing no conclusion about variant significance. c.9116C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Coulet_2010, Azzollini_2016, Rodriguez-Balada_2016, Park_2017, Guo_2020) but it was also reported in controls (Guo_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with BRCA2 pathogenic variants have been reported (BRCA2 c.658_659delGT, p.Val220IlefsX4; BRCA2 c.2808_2811delACAA, p.Ala938ProfsX21; via Internal testing and Santonocito_2020), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function through utilization of a homologous recombination DNA-repair activity assay, determined the variant to be neutral (Guidugli_2018, Hart_2019). Eight ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and two ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Sharing Clinical Reports Project (SCRP) RCV000083154 SCV000115228 likely benign Breast-ovarian cancer, familial 2 2013-06-25 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083154 SCV000147542 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Medical Genetics, University Hospital of North Norway RCV000083154 SCV000301455 uncertain significance Breast-ovarian cancer, familial 2 2016-05-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355960 SCV001550996 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Pro3039Leu variant was identified in 8 of 6754 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast and ovarian cancer and was not identified in 1586 control chromosomes from healthy individuals (Park 2017, Azzollini 2016, Rodriguez-Balada 2016, Jarhelle 2016, Llort 2002). The variant was identified in dbSNP (rs80359167) as “with likely benign, uncertain significance allele”, ClinVar (classified as likely benign by Invitae, GeneDx, Ambry Genetics and 7 other submitters, uncertain significance by BIC and 1 other submitter and benign by Color), LOVD 3.0 (observed 9x) and UMD-LSDB (observed 19x). The variant was identified in control databases in 22 of 248,254 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 6 of 30,496 chromosomes (freq: 0.0002), Latino in 6 of 34,364 chromosomes (freq: 0.0002), African in 2 of 16,040 chromosomes (freq: 0.0001), European in 8 of 111,594 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, and Other populations. The variant was observed in UMD-LSDB in a sample with a co-occurring BRCA1 pathogenic variant (c.670+1G>T). In cDNA amplification assays, the variant had no observed effect on in vitro splicing (Rodriguez-Balada 2016, Colombo 2012, Houdayer 2012, Menedez 2012). The p.Pro3039 residue is conserved in mammals but not in more distantly related organisms, and four out of five 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.Pro3039Leu variant occurs in the first 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, 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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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