ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9302T>G (p.Leu3101Arg) (rs28897758)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045787 SCV000073800 pathogenic Hereditary breast and ovarian cancer syndrome 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 3101 of the BRCA2 protein (p.Leu3101Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with breast or ovarian cancer, and has been shown to segregate with breast cancer in several families (Invitae, external communications). This variant also occurs in trans with a pathogenic variant (p.Ala938Profs*21) in BRCA2 in an individual with clinical features of Fanconi anemia (external communication). ClinVar contains an entry for this variant (Variation ID: 38230). An algorithm developed specifically for the BRCA2 gene suggests that this missense change is likely to be deleterious (PMID: 19043619). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000162632 SCV000213068 likely pathogenic Hereditary cancer-predisposing syndrome 2019-05-13 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
GeneDx RCV000657062 SCV000567965 likely pathogenic not provided 2018-12-04 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9302T>G at the cDNA level, p.Leu3101Arg (L3101R) at the protein level, and results in the change of a Leucine to a Glycine (CTG>CGG). Using alternate nomenclature, this variant would be defined as BRCA2 9530T>G. This variant was observed with a BRCA2 pathogenic variant in a patient with Fanconi anemia and in trans with a BRCA2 pathogenic variant in a fetus with symptoms consistent with Fanconi anemia (Dueber 2013, ClinVar VCV000038230.2). BRCA2 Leu3101Arg was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, we consider BRCA2 Leu3101Arg to be a likely pathogenic variant.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000485324 SCV000592275 uncertain significance not specified 2017-01-25 criteria provided, single submitter clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000045787 SCV000800821 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-13 criteria provided, single submitter clinical testing Data used in classification: The variant was observed in 10 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 16,600. The diagnosis of hereditary breast and/or ovarian cancer was confirmed in probands. The probands were confirmed as White British in all but two families (for which ethnicity not reported). Case control comparison against ethnically matched population data (10/16,600 in familial cases against 0/63,369 GNOMAD NFE controls) passoc=6.53x10-10 pexact= 1.49x10-7 (PS4_very strong). An additional 5 families have been identified in the UK (not included in the previous dataset).There are additional reports of this variant in ClinVar, BIC and BRCA2 LOVD. The variant is absent in the remainder of the GNOMAD populations (75,263 individuals) (PM2). In addition on testing in the UK of a fetus with a clinical diagnosis of Fanconi Anaemia D1, this variant was found in trans with a pathogenic truncating variant in BRCA2 (parental genotypes confirmed) (PM3). Predicted deleterious on AlignGVGD, SIFT, Polyphen2 HumVar (PP3).
Color RCV000162632 SCV000903964 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045787 SCV001362773 pathogenic Hereditary breast and ovarian cancer syndrome 2019-11-01 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9302T>G (p.Leu3101Arg) results in a non-conservative amino acid change located in the BRCA2, OB3 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250968 control chromosomes (gnomAD). c.9302T>G has been reported in the literature in individuals/families affected with Hereditary Breast and Ovarian Cancer (McRonald_2019, ClinVar SCV000800821.1), and also in individuals affected with Fanconi anemia who were reported with additional BRCA2 pathogenic variants presumed or confirmed to be in trans (Dueber_2013, ClinVar SCV000073800.8). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrate the variant to be damaging (Hart_2019). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic (n=3) and as uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031813 SCV000054421 uncertain significance Breast-ovarian cancer, familial 2 2012-05-15 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031813 SCV000147606 uncertain significance Breast-ovarian cancer, familial 2 2000-06-12 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.